Systems and interfaces for blood sampling

ABSTRACT

The present invention generally relates to systems and methods for delivering and/or receiving a substance or substances such as blood from subjects. In one aspect, the present invention is directed to devices and methods for receiving or extracting blood from a subject, e.g., from the skin and/or from beneath the skin, using devices containing a substance transfer component (for example, one or more needles or microneedles) and a reduced pressure or vacuum chamber having an internal pressure less than atmospheric pressure prior to receiving blood. In some embodiments, the device may contain a “snap dome” or other deformable structure, which may be used, at least in part, to urge or move needles or other suitable substance transfer components into the skin of a subject. In some cases, for example, the device may contain a flexible concave member and a needle mechanically coupled to the flexible concave member such that the needle may be urged or moved into the skin using the flexible concave member. Other aspects of the present invention are directed at other devices for receiving blood (or other bodily fluids, e.g., interstitial fluid), kits involving such devices, methods of making such devices, methods of using such devices, and the like.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 61/411,566, filed Nov. 9, 2010, entitled “Systemsand Interfaces for Blood Sampling,” by David Brancazio, incorporatedherein by reference.

FIELD OF INVENTION

The present invention generally relates to systems and methods fordelivering and/or receiving a substance or substances such as blood,from subjects, e.g., from the skin and/or from beneath the skin.

BACKGROUND

Phlebotomy or venipuncture is the process of obtaining intravenousaccess for the purpose of intravenous therapy or obtaining a sample ofvenous blood. This process is typically practiced by medicalpractitioners, including paramedics, phlebotomists, doctors, nurses, andthe like. Substantial equipment is needed to obtain blood from asubject, including the use of evacuated (vacuum) tubes, e.g., such asthe Vacutainer™ (Becton, Dickinson and company) and Vacuette™ (GreinerBio-One GmBH) systems. Other equipment includes hypodermic needles,syringes, and the like. However, such procedures are complicated andrequire sophisticated training of practitioners, and often cannot bedone in non-medical settings. Accordingly, improvements in methods ofobtaining blood or other fluids from the skin are still needed.

SUMMARY OF THE INVENTION

The present invention generally relates to systems and methods fordelivering and/or receiving a substance or substances such as blood,from subjects, e.g., from the skin and/or from beneath the skin. Thesubject matter of the present invention involves, in some cases,interrelated products, alternative solutions to a particular problem,and/or a plurality of different uses of one or more systems and/orarticles.

In one aspect, the invention is generally directed to a device forreceiving blood or other fluids from a subject. According to one set ofembodiments, the device includes a flexible concave member moveablebetween a first configuration and a second configuration, a needlemechanically coupled to the flexible concave member such that the needleis in a first position when the flexible concave member is in the firstconfiguration and the needle is in a second position when the flexibleconcave member is in the second configuration, an applicator regioncontaining the needle at least when the needle is in the secondposition, and a vacuum chamber having a pressure less than atmosphericpressure. In some embodiments, movement of the flexible concave memberfrom the first configuration to the second configuration creates a fluidcommunication pathway between the vacuum chamber and the applicatorregion.

The device, in another set of embodiments, includes a flexible concavemember moveable between a first configuration and a secondconfiguration, a needle mechanically coupled to the flexible concavemember such that the needle is in a first position when the flexibleconcave member is in the first configuration and the needle is in asecond position when the flexible concave member is in the secondconfiguration, an applicator region containing the needle at least whenthe needle is in the second position, a piercing member mechanicallycoupled to the flexible concave member such that the piercing member isable to move when the flexible concave member moves from the firstconfiguration to the second configuration, a vacuum chamber having apressure less than atmospheric pressure, and a pierceable surface influidic communication with the vacuum chamber. In some embodiments, thepiercing member is positioned to pierce the pierceable surface when thepiercing member is moved by the flexible concave member.

In yet another set of embodiments, the device includes a flexibleconcave member moveable between a first configuration and a secondconfiguration, an actuator able to move the flexible concave memberbetween the first configuration and the second configuration whenactuated, a needle mechanically coupled to the flexible concave membersuch that the needle is in a first position when the flexible concavemember is in the first configuration and the needle is in a secondposition when the flexible concave member is in the secondconfiguration, an applicator region containing the needle at least whenthe needle is in the second position, and a vacuum chamber having apressure less than atmospheric pressure. In certain embodiments, theactuator, when actuated, is able to create a fluid communication pathwaybetween the vacuum chamber and the applicator region.

The device, according to still another set of embodiments, includes aflexible concave member moveable between a first configuration and asecond configuration, an actuator able to move the flexible concavemember between the first configuration and the second configuration whenactuated, a needle mechanically coupled to the flexible concave membersuch that the needle is in a first position when the flexible concavemember is in the first configuration and the needle is in a secondposition when the flexible concave member is in the secondconfiguration, an applicator region containing the needle at least whenthe needle is in the second position, a piercing member mechanicallycoupled to the actuator, a vacuum chamber having a pressure less thanatmospheric pressure, and a pierceable surface in fluidic communicationwith the vacuum chamber. The piercing member, in some embodiments, ispositioned to pierce the pierceable surface when moved by the actuator.

In accordance with yet another set of embodiments, the device includes aflexible concave member moveable between a first configuration and asecond configuration, a needle mechanically coupled to the flexibleconcave member such that the needle is in a first position when theflexible concave member is in the first configuration and the needle isin a second position when the flexible concave member is in the secondconfiguration, an applicator region containing the needle at least whenthe needle is in the second position, and a vacuum chamber. In someembodiments, movement of the vacuum chamber creates a fluidiccommunication pathway between the vacuum chamber and the applicatorregion.

According to still another set of embodiments, the device includes aflexible concave member moveable between a first configuration and asecond configuration, a needle mechanically coupled to the flexibleconcave member such that the needle is in a first position when theflexible concave member is in the first configuration and the needle isin a second position when the flexible concave member is in the secondconfiguration, an applicator region containing the needle at least whenthe needle is in the second position, and a vacuum chamber. In certainembodiments, movement of the vacuum chamber causes movement of theflexible concave member from the first configuration to the secondconfiguration.

In one aspect, the present invention is generally directed to a simple,one-piece, low-profile, high acceleration, high energy, actuationmechanism for inserting microneedles (or other objects) into the skinfor the purpose of delivering or receiving bodily fluids, such as bloodor interstitial fluid.

In one set of embodiments, a device of the invention is actuated by adeployment actuator which can provide advantage in ease of operation,speed of operation, reduction or elimination of pain, etc.

In another aspect, the present invention is generally directed to adevice for receiving blood from the skin and/or from beneath the skin ofa subject. According to one set of embodiments, the device includes asubstance transfer component, a vacuum chamber having an internalpressure less than atmospheric pressure before blood is received intothe device, and a storage chamber, separate from the vacuum chamber, forreceiving blood from the subject via the substance transfer componentwhen a negative pressure is applied to the skin of the subject. Inanother set of embodiments, the device includes at least 6 microneedles,and a storage chamber for receiving blood from the subject. In certainembodiments, the storage chamber has an internal pressure less thanatmospheric pressure prior to receiving blood. The device, in yetanother set of embodiments, includes a plurality of microneedles havinga combined skin-penetration area of at least about 500 nm², and astorage chamber for receiving blood from the subject through theplurality of microneedles. The area may also be larger, for example, atleast about 2,500 micrometers. In some cases, the storage chamber has aninternal pressure less than atmospheric pressure prior to receivingblood.

In one set of embodiments, the device includes a deployment actuator, asubstance transfer component fastened to a deformable portion of thedeformable structure, and a storage chamber for receiving blood from thesubject via the substance transfer component. In certain instances, whenthe device is applied to the surface of the skin of a subject and thestructure is deformed, the substance transfer component is driven intothe skin of the subject. According to another set of embodiments, thedevice includes a deployment actuator, a substance transfer componentfastened to the deployment actuator, and a storage chamber for receivingblood from the subject via the substance transfer component. In somecases, the deployment actuator can insert the substance transfercomponent into the skin at a speed of at least about 1 cm/s. Higherspeeds may also be desirable in some embodiments, e.g., at least about 1m/s.

In another set of embodiments, the device includes a substance transfercomponent, a first storage chamber for receiving blood from the subjectvia the substance transfer component, and a second storage chamber forreceiving blood from the subject via the substance transfer component.In various embodiments, the first storage chamber may comprise a firstanticoagulant, and/or the second storage chamber may comprise a secondanticoagulant.

The device, according to yet another set of embodiments, includes asubstance transfer component, a first storage chamber for receivingblood from the subject via the substance transfer component, and areaction entity contained within the first storage chamber able to reactwith an analyte contained within the blood. In some cases, a product ofthe reaction entity with the analyte is determinable, and in certainembodiments, the storage chamber has an internal pressure less thanatmospheric pressure prior to receiving blood.

In one set of embodiments, the device includes a substance transfercomponent, a storage chamber for receiving blood from the subject viathe substance transfer component, and a potassium sensor able todetermine potassium ions within blood contained within the device. Insome embodiments, the storage chamber has an internal pressure less thanatmospheric pressure prior to receiving blood. In another set ofembodiments, the device includes a substance transfer component, astorage chamber for receiving blood from the subject via the substancetransfer component, and a flow controller able to control blood flowinto the storage chamber. In certain cases, the storage chamber has aninternal pressure less than atmospheric pressure prior to receivingblood.

According to yet another set of embodiments, the device includes asubstance transfer component, and a storage chamber for receiving fluidfrom the subject via the substance transfer component. In some cases,the device carries a color indicative of a recommended bodily use sitefor the device. The device, in still another set of embodiments,includes a substance transfer component for receiving fluid from thesubject, a storage chamber for receiving fluid from the subject via thesubstance transfer component, and an exit port for removing the fluidfrom the device, separate from the substance transfer component.According to yet another set of embodiments, the device includes asubstance transfer component for receiving fluid from the subject, and astorage chamber for receiving fluid from the subject via the substancetransfer component. In some embodiments, the device is constructed andarranged to reproducibly obtain from the subject, and deliver to ananalysis device, a fluid sample of less than about 1 ml. In another setof embodiments, the device includes a fluid sample device comprising asubstance transfer component for receiving fluid from the subject, and astorage chamber for receiving fluid from the subject via the substancetransfer component.

Another aspect of the invention involves a device able to receive asubstance or deliver a substance from or to a subject including atriggering mechanism able to move a substance transfer component,relative to the skin of a subject, in a short period of time, and/or ata relatively high velocity, and/or at a relatively high force, and/or ata relatively high pressure.

In yet another embodiment a device is provided in which a plurality ofskin insertion objects that are relatively small, are inserted to arelatively complete depth into and/or through the skin in routine deviceoperation.

According to another aspect, the invention is directed to an adaptorhaving a maximum length of no more than about 100 mm and a diameter ofno more than about 16 mm. In some embodiments, the adaptor is able toimmobilize a device having a largest lateral dimension of no more thanabout 50 mm, and/or a largest vertical dimension, extending from theskin of the subject when the device is applied to the subject, of nomore than about 10 mm.

In yet another aspect, the invention is directed to a kit. In one set ofembodiments, the kit includes a fluid sample device comprising asubstance transfer component for receiving fluid from the subject and astorage chamber for receiving fluid from the subject via the substancetransfer component, and an external analytical apparatus having a portfor mating with a port on the fluid sample device.

In another aspect, the present invention is directed to a method ofmaking one or more of the embodiments described herein, for example,devices for receiving blood from a subject. In another aspect, thepresent invention is directed to a method of using one or more of theembodiments described herein, for example, devices for receiving bloodfrom a subject.

Other advantages and novel features of the present invention will becomeapparent from the following detailed description of various non-limitingembodiments of the invention when considered in conjunction with theaccompanying figures. In cases where the present specification and adocument incorporated by reference include conflicting and/orinconsistent disclosure, the present specification shall control. If twoor more documents incorporated by reference include conflicting and/orinconsistent disclosure with respect to each other, then the documenthaving the later effective date shall control.

BRIEF DESCRIPTION OF THE DRAWINGS

Non-limiting embodiments of the present invention will be described byway of example with reference to the accompanying figures, which areschematic and are not intended to be drawn to scale. In the figures,each identical or nearly identical component illustrated is typicallyrepresented by a single numeral. For purposes of clarity, not everycomponent is labeled in every figure, nor is every component of eachembodiment of the invention shown where illustration is not necessary toallow those of ordinary skill in the art to understand the invention. Inthe figures:

FIGS. 1A-1B illustrate devices according to certain embodiments of theinvention;

FIGS. 2A-2C illustrate devices according to various embodiments of theinvention;

FIG. 2D illustrates a kit containing more than one device, in yetanother embodiment of the invention;

FIG. 2E illustrates a device according to still another embodiment ofthe invention;

FIG. 3 illustrates a device in one embodiment of the invention, having avacuum chamber;

FIG. 4 illustrates a device in another embodiment of the invention,having a vacuum chamber and a storage chamber;

FIG. 5 illustrates a device in yet another embodiment of the invention,having a flow controller;

FIG. 6 illustrates a device according to another embodiment of theinvention;

FIG. 7 illustrates a device in yet another embodiment of the invention,having an exit port;

FIG. 8 illustrates a device containing a fluid reservoir, in anotherembodiment of the invention;

FIG. 9 illustrates an adaptor according to one embodiment of theinvention;

FIGS. 10A-10C illustrate a device in still another embodimentillustrating a deployment actuator;

FIG. 11 illustrates yet another embodiment of the invention in which adevice is actuated by a deployment actuator;

FIGS. 12A and 12B illustrate yet another embodiment of the invention, inwhich a device is actuated by a deployment actuator, at different stagesof operation of the device; and

FIGS. 13A-13E illustrate several devices in accordance with variousembodiments of the inventions.

DETAILED DESCRIPTION

The present invention generally relates to systems and methods fordelivering and/or receiving a substance or substances such as blood fromsubjects. In one aspect, the present invention is directed to devicesand methods for receiving or extracting blood from a subject, e.g., fromthe skin and/or from beneath the skin, using devices containing asubstance transfer component (for example, one or more needles ormicroneedles) and a reduced pressure or vacuum chamber having aninternal pressure less than atmospheric pressure prior to receivingblood. In some embodiments, the device may contain a “snap dome” orother deformable structure, which may be used, at least in part, to urgeor move needles or other suitable substance transfer component into theskin of a subject. In some cases, for example, the device may contain asnap dome or other flexible concave member and a needle mechanicallycoupled to the flexible concave member such that the needle may be urgedor moved into the skin using the flexible concave member. Other aspectsof the present invention are directed at other devices for receivingblood (or other bodily fluids, e.g., interstitial fluid), kits involvingsuch devices, methods of making such devices, methods of using suchdevices, and the like.

The received fluid may be any suitable bodily fluid, such asinterstitial fluid, other skin-associated material, mucosal material orfluid, whole blood, perspiration, saliva, plasma, tears, lymph, urine,plasma, or any other bodily fluid, or combinations thereof. Substancesreceived from a subject can include solid or semi-solid material such asskin, cells, or any other substance from the subject. Substances thatcan be delivered to a subject in accordance with some embodiments of theinvention include diagnostic substances, therapeutic substances such asdrugs, and the like. Various embodiments of the invention are describedbelow in the context of delivering or receiving a fluid, such as blood,from or through the skin. It is to be understood that in all embodimentsherein, regardless of the specific exemplary language used (e.g.,receiving blood), the devices and methods of other embodiments of theinvention can be used for receiving any substance from the skin and/orfrom beneath the skin of the subject, and/or for delivering anysubstance to the subject, e.g. to the skin and/or a location beneath theskin of the subject.

In one aspect, the present invention is generally directed to devicesand methods for receiving or extracting blood or other bodily fluidsfrom a subject, e.g., from the skin and/or from beneath the skin, usingdevices containing a substance transfer component (for example, one ormore microneedles). The device may also contain, in some embodiments, astorage chamber having an internal pressure less than atmosphericpressure prior to receiving blood or other bodily fluids. In some cases,the device may pierce the skin of the subject, and fluid can then bedelivered and/or received from the subject. The subject is usuallyhuman, although non-human subjects may be used in certain instances, forinstance, other mammals such as a dog, a cat, a horse, a rabbit, a cow,a pig, a sheep, a goat, a rat (e.g., Rattus Norvegicus), a mouse (e.g.,Mus musculus), a guinea pig, a hamster, a primate (e.g., a monkey, achimpanzee, a baboon, an ape, a gorilla, etc.), or the like.

In some cases, the device can be applied to the skin, and activated toreceive fluid from the subject. The device, or a portion thereof, maythen be processed to determine the fluid and/or an analyte within thefluid, alone or with an external apparatus. For example, fluid may bereceived from the device, and/or the device may contain sensors oragents able to determine the fluid and/or an analyte suspected of beingcontained in the fluid.

The invention, in one set of embodiments, involves the determination ofa condition of a subject. Bodily fluids and/or other material associatedwith the skin may be analyzed, for instance, as an indication of a past,present and/or future condition of the subject, or to determineconditions that are external to the subject. Determination may occur,for instance, visually, tactilely, by odor, via instrumentation, etc. Inone aspect, accordingly, the present invention is generally directed tovarious devices for delivering and/or receiving blood, or other bodilyfluids, from the skin and/or from beneath the skin of a subject.Accordingly, in the description that follows, the discussion of blood isby way of example only, and in other embodiments, other fluids may bereceived from the skin in addition to and/or instead of blood.

In one set of embodiments, the device includes a substance transfercomponent able to deliver or receive fluid from the subject into thedevice. As used herein, “substance transfer component” is any componentor combination of components that facilitates movement of a fluid fromone portion of the device to another, and/or from the device to thesubject or vice versa. The substance transfer component may include anopening of any size and/or geometry that is constructed to receive fluidinto the device. For example, an opening of a substance transfercomponent may lie in a two-dimensional plane or the opening may includea three-dimensional cavity, hole, groove, slit, etc. In someembodiments, the substance transfer component may also include one ormore microneedles or other skin insertion objects, arranged to causefluid to be released from the subject, e.g., by piercing the skin of asubject.

For example, at or near the skin, a substance transfer component caninclude a hollow needle or a solid needle. If a solid needle is used,then if fluid migrates along the needle due to surface forces (e.g.,capillary action), then the solid needle can be part of a substancetransfer component. If fluid (e.g. blood or interstitial fluid)partially or fully fills an enclosure surrounding a needle afterpuncture of skin (whether the needle is or is not withdrawn from theskin after puncture), then the enclosure can define at least part of asubstance transfer component. A substance transfer component may includeany other suitable fluid transporter or flow activator. Other componentsincluding partially or fully enclosed channels, microfluidic channels,tubes, wicking members, vacuum containers, etc. can be, or be a part of,substance transfer components.

The fluid may be received from and/or through the skin of a subject (orother mucosal surface). The substance transfer component may include,for example, one or more needles and/or microneedles, a hygroscopicagent, a cutter or other piercing element, an electrically-assistedsystem, or the like, as discussed in detail herein. If needles ormicroneedles are used, they may be solid or hollow, i.e., blood or otherfluid may travel in and/or around the needles or microneedles into thedevice. In some cases, the needles or microneedles may also be removedfrom the subject, e.g., after insertion into the skin, for example, toincrease the flow of blood or other fluids from the subject. In one setof embodiments, the substance transfer component includes solid needlesthat are removed from the skin and a cup or channel to direct the flowof blood or other bodily fluids.

In some aspects, the device may include a support structure, such as ahousing. The housing may be used, as discussed herein, for applying thesubstance transfer component to the surface of the skin of the subject,e.g., so that fluid may be delivered and/or received from the skin ofthe subject. In some cases, the housing may immobilize the substancetransfer component such that the substance transfer component cannotmove relative to the housing; in other cases, however, the substancetransfer component, or a portion thereof, may be able to move relativeto the housing. In one embodiment, as a non-limiting example, thesubstance transfer component is immobilized relative to the housing, andthe deployment actuator is positioned within the device such thatapplication of the device to the skin causes at least a portion of thesubstance transfer component to pierce the skin of the subject. In somecases, as previously discussed, the housing encloses a deploymentactuator.

In some embodiments, the deployment actuator, or a portion of thedeployment actuator, may move from a first position to a secondposition. For example, the first position may be one where thedeployment actuator has attached thereto a substance transfer componentthat does not contact the skin (e.g., a skin insertion object of thesubstance transfer component may be contained within a recess of thesubstance transfer component), while the second position of thedeployment actuator may be one where the substance transfer componentdoes contact the skin, and in some cases, the substance transfercomponent may pierce the skin. The deployment actuator may be movedusing any suitable technique, e.g., manually, mechanically,electromagnetically, using a servo mechanism, or the like. In one set ofembodiments, for example, the deployment actuator may be moved from afirst position to a second position by pushing a button on the device,which causes the deployment actuator to move (either directly, orthrough a mechanism linking the button with the deployment actuator).Other mechanisms (e.g., dials, levers, sliders, etc., as discussedherein) may be used in conjunction of or instead of a button. In anotherset of embodiments, the deployment actuator may be moved from a firstposition to a second position automatically, for example, uponactivation by a computer, upon remote activation, after a period of timehas elapsed, or the like. For example, in one embodiment, a servoconnected to the deployment actuator is activated electronically, movingthe deployment actuator from the first position to the second position.In some cases, the deployment actuator may include a triggeringmechanism that initiates deployment.

In some cases, the deployment actuator and/or the substance transfercomponent may also be moved from the second position to the firstposition. For example, after fluid has been delivered and/or receivedfrom the skin, e.g., using a substance transfer component the deploymentactuator may be moved, which may move the substance transfer componentaway from contact with the skin. The deployment actuator may be movedfrom the second position to the first position using any suitabletechnique, including those described above, and the technique for movingthe deployment actuator from the second position to the first positionmay be the same or different as that moving the deployment actuator fromthe first position to the second position.

In some cases, the device may be able to draw skin towards the substancetransfer component. For example, in one set of embodiments, the devicemay include a vacuum interface or region. The interface or region may beconnected with a vacuum source (external and/or internal to the device),and when a vacuum is applied, skin may be drawn towards the device,e.g., for contact with a substance transfer component, such as one ormore needles or microneedles.

In one set of embodiments, the device includes a deployment actuatorable to drive a substance transfer component or a substance transfercomponent into the skin, e.g., so that the substance transfer componentcan receive a fluid from the skin and/or from beneath the skin of asubject, and/or so that the substance transfer component can deliver asubstance to a subject, e.g. deliver a substance to the skin and/or to alocation beneath the skin of a subject. The deployment actuator may be astructure that can be deformed using unaided force (e.g., by a humanpushing the structure), or other forces (e.g., electrically-appliedforces, mechanical interactions or the like), but is able to restore itsoriginal shape after the force is removed or at least partially reduced.For example, the deployment actuator may restore its original shapespontaneously, or some action (e.g., heating) may be needed to restorethe structure to its original shape. The deployment actuator may beformed out a suitable elastic material, in some cases. For instance, thedeployment actuator may be formed from a plastic, a polymer, a metal,etc. In one set of embodiments, the deployment actuator may have aconcave or convex shape. For instance, the edges of the deploymentactuator may be put under compressive stress such that the structure“bows” out to form a concave or convex shape. A person pushing againstthe concave or convex shape may deform the deployment actuator, butafter the person stops pushing on the deployment actuator, thedeployment actuator may be able to return to its original concave orconvex shape, e.g., spontaneously or with the aid of other forces aspreviously discussed. In some cases, the deployment actuator may bebistable, i.e., having two different positions in which the deploymentactuator is stable.

In one set of embodiments, the deployment actuator may include aflexible concave member or a reversibly deformable structure that ismoveable between a first configuration and a second configuration. Forinstance, the first configuration may have a concave shape, such as adome shape, and the second configuration may have a different shape, forexample, a deformed shape (e.g., a “squashed dome”), a convex shape, aninverted concave shape, or the like. See, for example, FIG. 10B. Theflexible concave member (or a deployment actuator) may be moved betweenthe first configuration and the second configuration manually, e.g., bypushing on the flexible concave member using a hand or a finger, and/orthe flexible concave member may be moved using an actuator such as isdescribed herein. In some cases, the flexible concave member may be ableto spontaneously return from the second configuration back to the firstconfiguration, e.g., as is shown in FIG. 10. In other cases, however,the flexible concave member may not be able to return to the firstconfiguration, for instance, in order to prevent accidental repeateduses of the flexible concave member. The flexible concave member, insome embodiments, may be a deployment actuator, although in otherembodiments, it need not be.

The flexible concave member (or a deployment actuator, in someembodiments) may be mechanically coupled to one or more needles (e.g.,microneedles), or other substance transfer components such as thosediscussed herein. If needles are used, the needles can be hollow orsolid, and there may be one or more than one needle. (It should beunderstood that in any embodiments described herein, references to aneedle are by way of simplicity, and in other embodiments, the devicecan include more than one needle (e.g., as in an array of needles),and/or the needle may be a microneedle.) The needle may be directlyimmobilized on the flexible concave member, or the needles can bemechanically coupled to the flexible concave member using bars, rods,levers, plates, springs, or other suitable structures. The needle (orother substance transfer component), in some embodiments, ismechanically coupled to the flexible concave member such that the needleis in a first position when the flexible concave member is in a firstconfiguration and the needle is in a second position when the flexibleconcave member is in a second configuration. Thus, movement of theflexible concave member (or deployment actuator) is able to cause theneedle to move from a first position to a second position. For instance,the first position of the needle may be a withdrawn position while thesecond position may be a deployed position where the needles are able tocontact and/or be inserted into the skin of a subject, for example, inan applicator region, for example, a recess within the device. In somecases, relatively high speeds and/or accelerations may be achieved,and/or insertion of the needle may occur in a relatively short period oftime, e.g., as is discussed herein. The first position and the secondposition, in some cases, may be separated by relatively small distances.For example, the first position and the second position may be separatedby a distance of less than about 10 mm, less than about 9 mm, less thanabout 8 mm, less than about 7 mm, less than about 6 mm, less than about5 mm, less than about 4 mm, less than about 3 mm, or less than about 2mm, etc. However, even within such distances, in certain embodiments,high speeds and/or accelerations such as those discussed herein can beachieved.

During use, a device may be placed into contact with the skin of asubject such that a recess or other suitable applicator region isproximate or in contact with the skin. By moving the flexible concavemember (or deployment actuator) between a first configuration and asecond configuration, because of the mechanical coupling, the flexibleconcave member is able to cause a needle (or other substance transfercomponent) to move to a second position within the recess or otherapplicator region and to contact or penetrate the skin of the subject.

In some embodiments, the device may also include a retraction mechanismable to move the needle (or other substance transfer component) awayfrom the skin after the flexible concave member (or a deploymentactuator) reaches a second configuration. Retraction of the flexibleconcave member may, in some embodiments, be caused by the flexibleconcave member itself, e.g., spontaneously returning from the secondconfiguration back to the first configuration, and/or the device mayinclude a separate retraction mechanism, for example, a spring, anelastic member, a collapsible foam, or the like. In some embodiments,the retraction mechanism may be useable only once or a limited number oftimes. For example, a spring or a collapsible foam may be used thatincludes a “breakaway” component, preventing reuse, or the spring may be“pre-packaged” within the device so that it can only be used once, andno mechanism is available within the device that allows the spring to bere-compressed.

The needle (or other substance transfer component) may be used fordelivering and/or receiving a substance or substances such as blood,from a subject, e.g., from the skin and/or from beneath the skin. Forexample, in some cases, a vacuum chamber having a reduced pressure or aninternal pressure less than atmospheric pressure prior to receivingblood or other bodily fluids (e.g., interstitial fluid) may be used toassist in the receiving of the fluid from the skin after the needle (orother substance transfer component) has penetrated the skin. The fluidreceived from the skin may be collected in the vacuum chamber and/or ina collection chamber. The collection chamber may be separated from thevacuum chamber using a gas permeable membrane (e.g., one that issubstantially impermeable to blood or other bodily fluids), ahydrophilic membrane, a porous structure, a dissolvable interface, orthe like, e.g., as is discussed herein.

In some cases, movement of a deployment actuator and/or a flexibleconcave member from a first configuration to a second configuration maybe used to create a fluid communication pathway between a vacuum chamberand an applicator region such as a recess that contains or is able tocontain needles or other substance transfer components for contact orinsertion into the skin of the subject. For example, a flexible concavemember and/or a deployment actuator may be mechanically coupled to apiercing member such that the piercing member is able to move when theflexible concave member moves from the first configuration to the secondconfiguration. The piercing member may be, for example, a needle, amicroneedle, a blade, a wire, or the like. As the flexible concavemember or deployment actuator moves, e.g., from a first configuration toa second configuration, the piercing member may be inserted or slid pastor into a pierceable surface. For example, the pierceable surface may bea foil or an airtight seal that is pierced, sliced, punctured, peeled,ripped, etc., or otherwise disrupted due to the movement of the piercingmember, e.g., into and/or across the pierceable surface. The pierceablesurface may separate a vacuum chamber from an applicator region suchthat, when disrupted, a fluid communication pathway is thereby createdbetween the vacuum chamber and the applicator region. In some cases,other methods may be used to disrupt the pierceable surface. In someembodiments, movement of a vacuum chamber, e.g., pushing on the vacuumchamber manually, or actuation involving movement of the vacuum chamber,may be used to cause disruption of the pierceable surface.

An example of a deployment actuator is now illustrated with respect toFIG. 10. In FIG. 10A, structure 700 has a generally concave shape, andis positioned on the surface of skin 710. In some cases, structure 700may be a flexible concave member. Structure 700 also contains aplurality of substance transfer components 720 for insertion into theskin. In FIG. 10B, a person (indicated by finger 705) pushes ontostructure 700, deforming at least a portion of the structure and therebyforcing substance transfer components 720 into at least a portion of theskin. In FIG. 10C, after the person releases structure 700, thestructure is allowed to return to its original position, e.g.,spontaneously, lifting substance transfer components 720 out of theskin. In some cases, e.g., if the substance transfer components aresufficiently large or long, blood or other fluids 750 may come out ofthe skin through the holes created by the substance transfer components,and optionally the fluid may be collected by the device for laterstorage and/or use, as discussed herein.

As another example, referring now to FIG. 11, a device 1100 isillustrated schematically in which a substance transfer componentcomprising a substance transfer component is driven by a deploymentactuator, such as a flexible concave member. In FIG. 11, device 1100includes a housing 1102 defining a plurality of chambers and channels.In other embodiments (not shown) a plurality of components that can beseparable from and attachable to each other (e.g., modular components)can together define the device and together define a series of channelsand compartments necessary for device function. See, e.g., U.S. patentapplication Ser. No. 12/716,233, filed Mar. 2, 2010, entitled “Systemsand Methods for Creating and Using Suction Blisters or Other PooledRegions of Fluid within the Skin,” by Levinson, et al.; U.S. patentapplication Ser. No. 12/716,226, filed Mar. 2, 2010, entitled“Techniques and Devices Associated with Blood Sampling,” by Levinson, etal.; or U.S. patent application Ser. No. 12/716,229, filed Mar. 2, 2010,entitled “Devices and Techniques Associated with Diagnostics, Therapies,and Other Applications, Including Skin-Associated Applications,” byBernstein, et al., each incorporated herein by reference.

In the specific device illustrated, device 1100 includes a surface 1104for positioning the device proximate the skin of a subject during use.Where desired in certain embodiments, the device can include an adhesivelayer 1106 where the adhesive is selected to be suitable for retainingthe device in a relatively fixed position relative to the skin duringuse, but may allow for relatively easy removal of the device from theskin following use. Specific non-limiting examples of adhesives arediscussed below. The adhesive also can be selected to assist inmaintaining a vacuum within portions of the device proximate the skin aswill be understood.

In FIG. 11, device 1100 includes a skin insertion object 1108. The skininsertion objects may be, for example, a substance transfer componentand/or a skin insertion object as discussed herein. Specificnon-limiting examples include needles or microneedles, e.g., as shown inFIG. 11. The substance transfer component can be or include, asdescribed elsewhere herein and in other documents incorporated herein byreference, any of a variety of components able to receive a substancefrom the skin and/or from beneath the skin of a subject, and or delivera substance to the skin and/or to a location beneath the skin of thesubject. For example, the substance transfer component may include oneor more needles and/or microneedles, a hygroscopic agent, a cutter orother piercing element, an electrically-assisted system, or the like. Inthe specific device illustrated, skin insertion objects 1108 define anarray of microinsertion objects such as solid or hollow microneedles. Inone set of embodiments, skin insertion object 1108 is selected to have aparticular size and profile for a particular use. For example, the skininsertion objects may include an array of insertion or microinsertionobjects which, in the device illustrated, emanate from a base 1110 whichwill be described further below.

In certain embodiments, a plurality of skin insertion objects 1108 arerelatively small, and are relatively completely driven into the skin.Examples of skin insertion objects include needles or microneedles,e.g., as described in greater detail below. The skin insertion objectsmay be positioned to address the skin of the subject, each protrudingfrom a base and defining a length from the base, and are able to beinserted into or through the skin to a depth essentially equal to theirlength but are prevented, by the base, from inserting at a depth greaterthan their length. In some embodiments, the plurality of skin insertionobjects have an average length (measured from the base) of no more thanabout 1,000 microns or more than about 2,000 microns, although lengthscan differ between individual skin insertion objects. In one set ofembodiments, the skin insertion objects are of relatively uniformlength, together defining an average length and each differing from theaverage length by no more than about 50%, about 40%, about 30%, about10%, or about 5%. The average length of the skin insertion objects, inother embodiments, are no more than about 1,500 microns, no more thanabout 1,000 microns, no more than about 900 microns, no more than about800 microns, no more than about 750 microns, no more than about 600microns, no more than about 500 microns, no more than about 400 microns,or no more than about 350 microns. In some embodiments, a triggeringmechanism as discussed herein is provided that is able to move the skininsertion objects from a fully predeployed position to a fully deployedposition with a force sufficient to insert the plurality of skininsertion object into or through the skin to an average depth of atleast about 50% the average length of the plurality of skin insertionobjects. In other embodiments, the triggering mechanism is able toinsert the plurality of skin insertion objects to an average depth of atleast about 55%, at least about 60%, at least about 65%, at least about70%, at least about 75%, at least about 80%, at least about 85%, atleast about 90%, at least about 92%, about 94%, about 96%, or about 98%of the average length of the plurality of skin insertion objects.

In the device illustrated, skin insertion objects 1108 are mounted on aflexible structure 1112 which, as illustrated, is maintained relativelyrigidly through various aspects of the device but which mounts skininsertion objects 1108 flexibly for up/down movement relative to theskin. Flexible structure 1112 can be a membrane, a single or multi-layerstructure selected from various polymers, metals, or the like to providesufficient properties such as any combination of flexibility,elasticity, gas permeability or impermeability, fluid permeability orimpermeability, or the like for desired operation. Portions of flexiblestructure 1112, skin insertion objects 1108, and other interior walls ofthe device define a region 1114 which allows for movement of skininsertion objects 1108 relative to the skin for delivery of a substanceto and/or receiving of a substance from the skin or beneath the skin,and, where a substance is received from the skin or from beneath theskin, region 1114 can serve as a reservoir for introduction of thesubstance into the device. Where a vacuum is used to receive a substancefrom the subject (as in the embodiment illustrated in FIG. 11), region1114, when positioned against the skin, can expose vacuum to thatportion of the skin proximate surface 1104 of the device and abuttingthe chamber.

Device 1100 also includes a device actuator 1116 which, as illustrated,includes a proximate portion 1118 which can be addressed by a user ofthe device (who may be the same or different from the subject the deviceis administered to) and a distal portion 1120 for addressing skininsertion objects 1108 via flexible structure 1112. Proximal portion1118 and distal portion 1120 are, in the device illustrated, oppositeends of a single component but, as would be understood by those ofordinary skill in the art, the actuator can include a plurality ofindividual components operably linked in any way necessary to performactuation as will be described.

As will be understood, FIG. 11 is a cross-section of a deviceillustrating various components and channels within the device. As willalso be understood by those of ordinary skill in the art, differentarrangements of devices and channels are contemplated herein so long asthe purpose of the device described herein is met. In this figure,device actuator 1116 is directly connected to or otherwise operablylinked to a deployment actuator 1122 which, in the device illustrated,is in the form of a “snap dome,” the function and use of which will bedescribed below. The snap dome in this figure has an approximatelycircular profile, and may define in some embodiments a flexible concavemember. The structure may define an interior and a periphery which, ifnot circular, may include a plurality of tabs, protrusions, or the likesufficient for support of structure 1122 within the device. Asillustrated, a plurality of tabs (or the essentially circular perimeterof) the device are supported within holders 1124, and the center, snapdome portion of the device is operably linked to device actuator 1116,such that movement of the central portion of snap dome 1122 and theperiphery of the snap dome can be controlled independently of eachother. Holders 1124 are directly connected to or otherwise operablylinked to an actuator retraction component 1126 which, in the deviceillustrated, can be a ring-shaped structure positioned under andsupporting holders 1124. Holders 1124 can be individual holders and/or aring-like structure surrounding the periphery of snap dome 1122. Aseries of one, two, or more support members (e.g., 1130) are positionednear the top of device 1100 and serve to define a series of channels forsample flow, vacuum control, or the like as will be described.

Turning now to channels defined within the device, as described above,region 1114, when the device is positioned against skin, can serve toexpose a portion of the skin defined by the periphery of the region to avacuum, to skin insertion objects 1108 as they move toward and/or awayfrom the skin, and/or to transfer a substance from or to the subject.Region 1114 can house a substance for transfer to the subject, in theform of a pharmaceutical composition or the like, optionally loaded onskin insertion objects 1108. Where blood and/or interstitial fluid isdrawn from a subject, region 1114 can serve to introduce the substanceinto the device from the subject.

A channel 1132 connects region 1114 to other portions of the device inthis example. Channel 1132 can be used to deliver a substance to region1114 for transfer to a subject, or for application of a vacuum to region1114, and/or for receiving a substance from a subject. The remainder ofthe description of device 1100 will be made within the context ofreceiving a substance such as blood and/or interstitial fluid from asubject, but it is to be understood that substances can also bedelivered via various channels. Channel 1132 typically emanates in onedirection from region 1114 although a plurality of channels can emanatefrom the region, arranged radially or otherwise relative to the centerof the device. In device 1100, channel 1132 first passes laterally fromthe center of the device and then upwardly where, near the top of thedevice, it can, optionally, include one wall defining a window 1134through which a user of the device can observe transfer of a substance,or through which analysis of a substance may occur. It can also itselfdefine a reservoir, in whole or in part, or be connected to an internalor an external reservoir for maintaining, storing, and/or transferring asubstance drawn from a subject. As shown here, it can be connected to asubstance collection reservoir 1136 which, as illustrated, is adisc-shaped reservoir formed in the device housing and surrounding thecenter of the device including device actuator 1116 and relatedcomponents.

Device 1100, illustrated as one example of devices provided by theinvention, includes a vacuum chamber for applying a vacuum proximate theskin of a subject for receiving a substance from the skin. Asillustrated, vacuum chamber 1138 is positioned in a central portion ofthe device surrounding device actuator 1116, although it can be providedanywhere in or proximate the device. The vacuum chamber can be evacuatedto an appropriate level just prior to use, or the device can bepre-packaged under vacuum as described elsewhere herein. As illustrated,vacuum chamber 1138 is in fluid communication with substance collectionreservoir 1136 but, in its initial state and prior to use, a membrane orother component, such as support member 1128, separates channel 1132connecting it to region 1102. In the device illustrated, a vacuumactuation component 1140 can be actuated to puncture the membrane orother component (e.g., 1128) and thereby connect vacuum chamber 1138with channel 1132, at an appropriate time during use of the device. Inother embodiments, device actuator 1116 and vacuum actuation component1140 can be combined into a single button or operably linked so thatonly one operation is needed to actuate both the microinsertion objectsand the vacuum.

Deployment actuator (or, as shown, a snap dome or other flexible concavemember) 1122 can be provided in a variety of forms including amonostable or bistable configuration. In the embodiment illustrated, abistable configuration is illustrated including first and second lowenergy or stable configurations separated by a relatively high energy orunstable configuration. As shown, deployment actuator 1122 is shown in a“cocked” or predeployed position.

The deployment actuator (or the flexible concave member) may be formedfrom any suitable material, for example, a metal such as stainless steel(e.g., 301, 301LN, 304, 304L, 304LN, 304H, 305, 312, 321, 321H, 316,316L, 316LN, 316Ti, 317L, 409, 410, 430, 440A, 440B, 440C, 440F, 904L),carbon steel, spring steel, spring brass, phosphor bronze, berylliumcopper, titanium, titanium alloy steels, chrome vanadium, nickel alloysteels (e.g., Monel 400, Monel K 500, Inconel 600, Inconel 718,Inconel×750, etc.), a polymer (e.g., polyvinylchloride, polypropylene,polycarbonate, etc.), a composite or a laminate (e.g., comprisingfiberglass, carbon fiber, bamboo, Kevlar, etc.), or the like. Thedeployment actuator may be of any shape and/or size. In one embodiment,the deployment actuator is a flexible concave member. The deploymentactuator may have, for instance, a generally domed shape (e.g., as in asnap dome), and be circular (no legs), or the deployment actuator mayhave other shapes, e.g., oblong, triangular (3 legs), square (4 legs),pentagonal (5 legs), hexagonal (6 legs), spiderlegged, starlike,clover-shaped (with any number of lobes, e.g., 2, 3, 4, 5, etc.), or thelike. The deployment actuator may have, in some embodiments, a hole, aport, a slot, dimple, or button in the middle. The deployment actuatormay also have a serrated disc or a wave shape. In some cases, the skininsertion objects may be mounted on the deployment actuator. In othercases, however, the skin insertion objects are mounted on a separatestructure which is driven or actuated upon movement of the deploymentactuator.

In one set of embodiments, the deployment actuator is not planar, andhas a portion that can be in a first position (a “cocked” or predeployedposition) or a second position (a “fired” or deployed position),optionally separated by a relatively high energy configuration. In somecases, both the first position and the second position are stable (i.e.,the structure is bistable), although conversion between the firstposition and the second position requires the structure to proceedthrough an unstable configuration.

In some cases, surprisingly, the distance or separation between thefirst position and the second position of the deployment actuator or theflexible concave member is relatively small. Such distances orseparations may be achieved using snap domes or other configurationssuch as those described herein, in contrast to springs or other deviceswhich require longer translational or other movements. For example, theperpendicular distance (i.e., in a direction away from the skin) in thedeployment actuator between the top of the structure and the bottom ofthe structure (excluding the skin insertion objects) when the devicecontaining the structure is placed on the skin of a subject may be nomore than about 5 mm, no more than about 4 mm, no more than about 3 mm,no more than about 2 mm, no more than about 1 mm in some cases, no morethan about 0.8 mm, no more than about 0.5 mm, or no more than about 0.3mm. In one set of embodiments, the distance is between about 0.3 mm andabout 1.5 mm. In another set of embodiments, the deployment actuator mayhave a greatest lateral dimension (parallel to the skin) when the devicecontaining the structure is placed on the skin of a subject of no morethan about 50 mm, no more than about 40 mm, no more than about 30 mm, nomore than about 25 mm, no more than about 20 mm, no more than about 15mm, no more than about 5 mm, no more than about 4 mm, no more than about3 mm, no more than about 2 mm, no more than about 1 mm in some cases, nomore than about 0.8 mm, no more than about 0.5 mm, or no more than about0.3 mm. In one set of embodiments, the distance is between about 0.3 mmand about 1.5 mm.

Use of device 1100 will now be described in the context of receiving asubstance such as blood from a subject. Device 1100 is placed againstthe skin of a subject such that at least a portion of surface 1104contacts the skin. Prior to use, a cover member (not shown) can coversurface 1104 of the device and can cover region 1114, to protect surface1104 and region 1114 from contaminants, etc. optionally maintaining theinterior of the device in a sterile condition. The cover can be peeledoff or otherwise removed from the device, and the device placed againstthe skin, optionally adhering to the skin. Vacuum actuation component1140 can be actuated to expose channel 1132 and region 1114 to vacuum atany time, including before, simultaneously, or after actuation of skininsertion objects 1108. In one arrangement, vacuum actuation component1140 is actuated to apply vacuum to region 1114 prior to actuation toskin insertion objects 1108, thereby to create a vacuum against the skinproximate region 1114 prior to use. Actuation of device actuator 1116can take place before or after deployment of vacuum.

When device actuator 1116 is actuated by a user (e.g., when proximalportion 1118 is depressed downwardly as shown in the figure), distalportion 1120 engages skin insertion objects 1108 (optionally viaflexible structure 1112) to drive them toward the skin. In someembodiments, foil 1128 is first broken, then component 1126 iscompressed, then component 1126 is broken, before flexible structure1112 is stretched and the deployment actuator 1122 of the device firesor is actuated. Membranes or other members 1112, 1128, or 1130 may have,in some cases, sufficient flexibility and/or elasticity to allow deviceactuator 1116 to drive skin insertion objects 1108 sufficiently distally(downwardly, as shown) to engage the skin of the subject and carry outthe desired function of the device. Various gaskets, bearings, ormembranes as shown can be used for this function. Where support member1128 is a foil or the like used for the purpose of initially separatingvacuum reservoir 1138 from channel 1132 (e.g., prior to use), whendevice actuator 1116 is moved downwardly, vacuum actuation component1140 may rupture support member 1128 proximate device actuator 1116, orflexibly deform as need be, so long as member 1130 (or anothercomponent) serves to allow device actuator 1116 to move slidably withinthe device while maintaining sufficient vacuum in vacuum reservoir 1138and related channels for use of the device.

When skin insertion objects 1108 engage the skin of the subject andfacilitates receiving a substance from the skin and/or from beneath theskin of the subject, a vacuum can draw the substance into region 1114,through channel or channels 1132, and into substance collectionreservoir 1136. In this process, device actuator 1116 first urges ormoves structure 1122 from its first stable configuration to a relativelyunstable configuration and beyond that point, at which point thestructure 1122 rapidly moves to a second stable configuration associatedwith downward driving of device actuator 1116 to quickly drive accessskin insertion objects 1108 proximate the skin.

After that point, if it is desirable for skin insertion objects 1108 tobe withdrawn from the skin, then a variety of techniques can be used todo so. In the device illustrated, retraction component 1126 drivesholder 1124 upwardly, retracting structure 1122 and device actuator 1116from skin insertion objects 1108. At that point, device actuator 1116can be operably linked to skin insertion objects 1108 and receive thetransfer component, or it can move freely relative to skin insertionobjects 1108, whereby flexible structure 1112 (e.g., an elasticmembrane) or other component can withdraw skin insertion objects 1108from the skin. Again, in the device illustrated, retraction component1126 can itself be a deployment actuator such as a leaf spring, coilspring, foam, or the like. During use, when device actuator 1116 isdriven downwardly, retraction component 1126 is first compressed and,depending upon the size and arrangement of components 1126, 1124, 1122,1116 and 1108, during compression, skin insertion objects 1108 can bedriven downwardly to some extent. At the point at which retractioncomponent 1126 is compressed and provides a sufficient resistance force,deployment actuator 1122 can be urged or moved from its firstconfiguration through an unstable configuration and can return to itssecond configuration, driving skin insertion objects 1108 against theskin. Then, upon release of user pressure (or other actuation, which canbe automatic) from device actuator 1116, retraction component 1126 canexpand and, with structure 1122 optionally remaining in its second,downwardly-driven low-energy configuration, device actuator 1116 can beretracted and skin insertion objects 1108 retracted from the skin.

Referring now to FIGS. 12A and 12B, device 1150 is illustratedschematically. Device 1150 is similar to and can be consideredessentially identical to device 1100 in all aspects other than thosedescribed here with respect to FIGS. 12A and 12B. As such, the readerwill observe that not all components are provided, although othercomponents similar to those of device 1100 can exist. One way in whichdevice 1150 differs from device 1100 is that in device 1150, in thepre-deployment or post-deployment retracted configuration, membrane 1112is drawn proximally (upwardly) as illustrated in FIG. 12B. Membrane 1112is in a less-stressed lower-energy configuration as shown in FIG. 12Awhen retraction component 1126 is compressed and skin insertion objects1108 are driven proximate the skin. Devices 1100, 1150, and othersimilar devices are one way to enact a triggering mechanism that canmove skin insertion objects 1108 or other similar transfer componentrelative to the skin in particularly advantageous ways. Examples oftriggering mechanisms include, in addition to the examples shown inFIGS. 11 and 12, blasting caps, explosives, other chemical reactions,solenoids or other electrical interactions, pneumatics (e.g., compressedair), other thermal interactions or mechanical interactions, or thelike.

In one set of embodiments, the triggering mechanism may move skininsertion objects 1108 from a fully predeployed position (e.g., as shownin FIG. 11) to a fully deployed position in which skin insertion objects1108 are fully engaged with the skin, in a short period of time. In oneembodiment, that period of time is less than about 0.01 seconds, and inother embodiments, less than about 0.009 seconds, less than about 0.008seconds, less than about 0.007 seconds, less than about 0.006 seconds,less than about 0.005 seconds, less than about 0.004 seconds, less thanabout 0.003 seconds, less than about 0.002 seconds, less than about0.001 seconds, less than about 0.0005 seconds, less than about 0.00025,or less than about 0.0001 seconds.

In another embodiment, skin insertion objects 1108 move quickly relativeto skin during deployment via the triggering mechanism, reaching a speedof at least about 4 m/s, at least about 5 m/s, at least about 6 m/s, atleast about 7 m/s, at least about 8 m/s, at least about 10 m/s, at leastabout 12 m/s, at least about 15 m/s, or at least about 20 m/sat thepoint at which skin insertion objects 1108 first touch the skin duringdeployment.

In some cases, skin insertion objects 1108 achieve relatively highaccelerations due to the triggering mechanism, for example, at leastabout 4 m/s², about 6 m/s², about 8 m/s², about 10 m/s², about 12 m/s²,about 15 m/s², or about 20 m/s², at least about 30 m/s², at least about50 m/s², at least about 100 m/s², at least about 300 m/s², at leastabout 500 m/s², at least about 1,000 m/s², at least about 3,000 m/s², atleast about 5,000 m/s², at least about 10,000 m/s², at least about30,000 m/s², at least about 50,000 m/s², at least about 100,000 m/s², atleast about 200,000 m/s², or at least about 300,000 m/s². In someembodiments, the skin insertion objects 1108 are accelerated forrelatively short periods of time, e.g., less than about 1 s, less thanabout 300 ms, less than about 100 ms, less than about 30 ms, less thanabout 10 ms, less than about 3 ms, or less than about 1 ms, and/or overrelatively short distances, e.g., less than about 5 mm, less than about4 mm, less than about 3 mm, less than about 2 mm, less than about 1 mm,less than about 800 micrometers, less than 600 micrometers, less than500 micrometers, less than 400 micrometers, less than about 300micrometers, less than about 200 micrometers, less than about 100micrometers, less than about 50 micrometers, etc.

Significant forces can be applied to skin insertion objects 1108 as theymove relative to the skin via the triggering mechanism. In another setof embodiments, skin insertion objects 1108, at the point at which theyfirst contact the skin, are driven by a force created at least in partby the triggering mechanism of at least about 6 micronewtons, about 8micronewtons, about 10 micronewtons, about 12 micronewtons, or about 15micronewtons.

In another set of embodiments, skin insertion objects 1108 apply apressure to the skin, during deployment caused by the triggeringmechanism, of at least about 100 N/m², at least about 300 N/m², at leastabout 1,000 N/m², at least about 3,000 N/m², etc. In force assessment,the area can be measured as the area of skin displaced by the transfercomponent at full deployment, e.g., the area of the skin ruptured by thetotal of the cross sectional area of all skin insertion objects insertedinto the skin, at the top surface of the skin.

In some cases, the skin insertion objects are forced into the skin viathe triggering mechanism with a force sufficient to insert the skininsertion objects into or through the skin to an average depth of atleast about 60% of the skin insertion object (or the average length ofthe skin insertion objects, if more than one is used, e.g., as in anarray of microneedles). In some cases, the depth is at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85%, at least about 90%, or at least about 95% of the skininsertion objects, e.g., the length of the needle or the microneedleinserted into the skin.

Referring now to FIG. 13, various examples of devices including flexibleconcave members are now discussed. In FIG. 13A, a device 900 forreceiving blood or other fluids from a subject is shown positioned ontothe skin 999 of a subject. Device 900 includes first module 905 andsecond module 910. First module 905 includes vacuum chamber 907, andoptionally, collection chamber 908, which can be used to collect bloodor other bodily fluids from the subject. When the device is used tofluids from a subject, vacuum chamber 907 may be used to urge or movethe fluid from the subject into the device, and into collection chamber908 and/or vacuum chamber 907.

First module 905 can, in some embodiments, be detached from secondmodule 910, and replaced with a fresh first module 905, for example, forrepeated uses of the device. First module 905, as is shown in FIG. 13A,includes a substantially cylindrical vacuum chamber 907, and, withinvacuum chamber 907, collection chamber 908. In other embodiments,however collection chamber 908 may be positioned elsewhere within thedevice besides within vacuum chamber 907, including within module 910.Vacuum chamber 907 may be, for example, a Vacutainer™ tube, a Vacuette™tube, or other similar vacuum tube, many of which are commerciallyavailable.

As mentioned, in some cases, collection chamber 908 may be positionedwithin the vacuum chamber 907. Collection chamber 908 may thus have ashape that fits substantially inside of vacuum chamber 907. In somecases, collection chamber 908 may also be removable from vacuum chamber907, for example, for analysis of blood or other bodily fluids receivedfrom the subject. In other cases, however, collection chamber 908 maynot be easily removed from vacuum chamber 907.

As is shown in FIG. 13A, passages 906 allow vacuum chamber 907 andcollection chamber 908 to be in fluidic communication. Passages 906 maybe, for example, holes, tubes, or other suitable openings that allow thetwo chambers to be in fluidic communication with each other. Thus, thetwo chambers may have substantially the same pressure (i.e.,substantially the same reduced pressure), such that, when the reducedpressure causes blood or other bodily fluids to flow into first module905, the fluid first enters the collection chamber 908. In some cases,collection chamber 908 may be separated from vacuum chamber 907 using agas permeable membrane, a hydrophilic membrane, a porous structure, adissolvable interface, or the like, i.e., to prevent blood or otherbodily fluids from exiting collection chamber 908 into vacuum chamber907. Passage 906 could be positioned anywhere along chamber 908,including the top of chamber 908 in the orientation shown in FIG. 13A.

First module 905 also contains, at one end, a surface or a seal 909 thatcan be pierced as is discussed below. Before use, first module 905 maybe separate from second module 910, and this end of first module 905 maybe sealed using surface 909, thereby preventing the loss of reducedpressure from within vacuum chamber 907, prior to use of the firstmodule 905 within device 900. The pierceable surface may be, forexample, a foil, a metal, a polymer, rubber, a rubber septum, or thelike that can be pierced by a piercing member 912 from second module910, as is discussed below.

First module 905 may be connected to second module 910 to form device900. When first module 905 is connected to second module 910, piercingmember 912 is inserted into pierceable surface 909 as first module 905and second module 910 are connected to each other. Piercing member 912may be, for example, a needle, a microneedle, a blade, or other piercingstructure that is able to penetrate the pierceable surface 909 whenfirst module 905 and second module 910 are connected. Piercing member912 may be, e.g., a hollow needle, and in some cases, piercing member isin fluidic communication with applicator region 940. Once piercingmember 912 has been inserted into (or otherwise disrupted) pierceablesurface 909, a fluidic connection may be formed between vacuum chamber907, and a fluid received from the skin of a subject, e.g., withinapplicator region 940, as is discussed below.

When first module 905 and second module 910 are connected, a surface offirst module 905 pushes down on one or more activation members 916 as isshown in FIG. 13A. In this example activation member 916 has a generallycylindrical shape that is pushed down onto flexible concave member 920.Activation members 916 then can be used to move flexible concave member920, as is discussed below. In other embodiments, other mechanicalcouplings may be used in addition to or instead of activation members,for example, levers, gears, or the like. The surface used to moveactivation members 916, as is shown in FIG. 13A, is the same pierceablesurface as discussed above that is pierced by piercing member 912 whenfirst module 905 and second module 910 are connected. However, in otherembodiments, other surfaces may be used, or the portions used to pushactivation members 916 may be different than the pierceable surface offirst module 905 that is pierced by piercing member 912.

Activation members 916, in the example illustrated in FIG. 13A, push aflexible concave member 920, e.g., a “snap dome,” or other suitablestructure, for example, a deformable structure (e.g., a deploymentactuator) such as described herein. In the example of FIG. 13A, flexibleconcave member 920 can be in either a first configuration or a secondconfiguration, where the first configuration is “concave down” while thesecond configuration is “concave up.” In FIG. 13A, the secondconfiguration of flexible concave member 920 is shown. Due to theconcave shape of the flexible concave member, and/or the materials usedto form the flexible concave member, the flexible concave member cannotadopt a stable configuration in a position midway between the firstconfiguration and the second configuration, or in other words, theflexible concave member is able to “snap” from the first configurationto the second configuration. This movement of flexible concave member920 from the first configuration to the second configuration, as shownin FIG. 13A, is caused by activation members 916 pushing against asurface of the flexible concave member. Accordingly, by connecting firstmodule 905 and second module 910, the activation members 916 are pushedby a surface of first module 905 into flexible concave member 920,thereby causing flexible concave member 920 to “snap” from the firstconfiguration to the second configuration. In some cases, this actionmay be quite rapid, as is discussed herein. In other embodiments (notshown here), the connection of the components may be used to load thedevice by compressing a component. In some cases, the actual firing iscontrolled by a release mechanism (e.g., a button).

Flexible concave member 920, in the example shown in FIG. 13A, ismechanically coupled to a microneedle array 930 via activation ring 925.In this case, microneedles 930 may be formed or attached to a plate 932that can be moved as activation ring 925 and/or flexible concave member920 are moved. In other embodiments, however, other mechanical couplingsmay be used to mechanically couple the flexible concave member and themicroneedle array, or in some cases, microneedles 930 may be directlyattached to flexible concave member 920. Examples of other mechanicalcoupling systems that can be used include, but are not limited,activation members, levers, gears, or the like. In addition, although anarray of microneedles 930 is shown in FIG. 13A (connected to plate 932),the invention is not so limited, and in other embodiments, othersubstance transfer components can be used, for example, needles or othersubstance transfer components as discussed herein. In this example, whenflexible concave member 920 moves from the first configuration to thesecond configuration, due to the transfer of energy or momentum fromflexible concave member 920 to plate 932 via activation ring 925, themicroneedles 930 are driven rapidly downward. Initially, activation ring925 would be in a raised position in FIG. 13A, and would be pusheddownward during actuation, e.g., to activate plate 932 and microneedles930 by momentum transfer or the like. In some cases, spring 964 may beused to hold activation ring 925 in a raised position prior to use. Inthis example, such movement causes the microneedles to become moved to alower position in which the microneedles are able to contact the skin ofa subject in applicator region 940, and preferably inserted orpenetrated into the skin of the subject. In some cases, optionally, themicroneedles may also be withdrawn from the skin after insertion, forexample, due to the flexible concave member returning to the firstconfiguration, and/or due to the presence of a retraction mechanism. Forexample, as is shown in FIG. 13A, when module 905 is attached to module910, module 905 may be pushed hard enough to compress spring 964, whichallows activation members 916 to press down on flexible concave member920. This in turn compresses spring 966, positioning needles 930 abovethe skin 999. With additional force, activation members 916 causesflexible concave member 920 to snap into its second configuration, whichinserts needles 930 into the skin 999. When force is released frommodule 905, spring 966 raises activation members 916 and module 905, andspring 966 raises flexible concave member 920, causing plate 932 andneedles 930 to retract from skin 999. In some embodiments, however,plate 932 may be elastomeric and thus could also function as aretraction mechanism (or as part of a retraction mechanism, e.g., incombination with the configuration shown in FIG. 13A).

Once microneedles 930 have been inserted into the skin, bleeding mayoccur. In the example illustrated in FIG. 13A, the blood may flow fromthe skin into applicator region 940. In this figure, piercing member 912is a hollow shaft that extends from vacuum chamber 907 through secondmodule 910 to applicator region 940. Because of the action of the vacuumfrom vacuum chamber 907, blood is drawn through hollow piercing member912 into collection chamber 908 to be collected therein. Otherconfigurations for the removal of blood or other fluids may be used inother embodiments. For instance, a channel that circumvents the needlearray and snap dome may be used in some cases.

In some cases, vacuum chamber 907 and/or collection chamber 908 may beclear or substantially clear, thereby allowing monitoring of thereceiving fluids such as blood from the subject to occur. Thus, forexample, when collection chamber 908 is filled or partially filled to acertain extent, the device can be removed from the skin of the subject.

After a suitable time, for example, when collection chamber 908 isfilled with blood, or partially filled to a certain or predeterminedextent, device 900 can be removed from the skin of the subject. Inaddition, first module 905 and second module 910 may be removed fromeach other, so that the blood within blood collection chamber 908 can beanalyzed using suitable techniques such as those described herein. Forexample, vacuum chamber 907 may be a Vacutainer™ tube or a Vacuette™tube as previously described, and first module 905 may thus beinterfaced with standard commercially-available equipment able toprocess Vacutainer™ tubes or a Vacuette™ tubes. In some cases, thecollection chamber may be removed from the vacuum chamber 907 for lateranalysis.

Another example of a device including a flexible concave member isillustrated in FIG. 13B. Like the device illustrated in FIG. 13A, FIG.13B shows device 900 positioned on skin 999, including a first module905 and a second module 910 that can be connected to each other to formdevice 900. In this figure, first module 905 includes vacuum chamber907, which may be a Vacutainer™ tube or a Vacuette™ tube, or othersimilar tube or vacuum chamber as is described herein. Many othercomponents, including collection chamber 908, are present within secondmodule 910. In this example, vacuum chamber 907 has a septum 902 thatcovers an end of vacuum chamber 907, and thereby allows vacuum chamber907 to retain its reduced pressure prior to use. In some cases, septum902 may be part of the Vacutainer™ tube or a Vacuette™ tube. Optionally,a cap may be present on first module 905, as is illustrated with cap 903in FIG. 13B. In some cases, cap 903 may include an opening 904 to allowthe insertion of a piercing member 912 into septum 902. At the end ofsecond module 910 may be a cap 903 (or a shield in some cases) that canbe used to at least partially protect an end of second module 910,including needles 930, e.g., before or after use. Cap 903 may form aseal with vacuum chamber 907 and also may be able to slide into body 919of second module 910 while keeping such a seal intact.

During use, first module 905 is connected to second module 910 such thatpiercing member 912 on first module 905 is inserted through septum 902of second module 910 into the reduced pressure environment of vacuumchamber 907. Piercing member 912 can be, for example, a hollow needle,and insertion of piercing member 912 allows a fluidic connection withthe reduced pressure within vacuum chamber 907 to be formed.

Second module 910 contains similar components as those previouslydescribed with respect to FIG. 13A, including a flexible concave member920 that is moved from a first configuration to a second configurationupon the connection of second chamber 907 with second module 910. Thesecond configuration is illustrated in FIG. 13B. The body 919 of secondmodule 910 may be formed out of any suitable material, for example, apolymer, rubber, or the like. Unlike FIG. 13A, in FIG. 13B, noactivation members are used, and cap 903 is directly used to move theflexible concave member from a first configuration to a secondconfiguration, e.g., by having a portion of cap 903 pushing against aportion of flexible concave member 920. Spring 964 is used in FIG. 13Bto push cap 903 back to its original position once spring 964 iscompressed due to movement of cap 903 downwardly into flexible concavemember 920.

However, spring 966 is compressed and can function as a retractionmechanism when flexible concave member 920 is moved from the firstconfiguration to a second configuration, similar to the above discussionwith reference to FIG. 13A.

As flexible concave member 920 is moved from the first configuration toa second configuration, flexible concave member 920 is able to moveactivation members 924, which causes plate 932 having one or moreneedles 930 attached thereon to move from a first position to a secondposition. Thus, needles 930 are in a first position when flexibleconcave member 920 is in a first configuration, and needles 930 are in asecond position when flexible concave member 920 is in a secondconfiguration. The second position is shown in FIG. 13B. Needles 930 arepresent within applicator region 940, which, in this example, is presentas a recess within device 900.

As the needles move from the first position to the second position, theneedles may contact or may be inserted into the skin of a subject, insome cases allowing blood to be drawn from the subject. The blood fromthe subject is then urged or moved into second module 910, and inparticular, into collection chamber 908 within second module 910.Collection chamber 908 is positioned such that it is in fluidiccommunication with piercing member 912, which, in this embodiment, is ahollow needle, i.e., blood flows from applicator region 940 directlyinto a first end collection chamber 908, while an opposing end ofcollection chamber 908 is in fluidic communication with the reducedpressure environment of vacuum chamber 907 via piercing member 912,thereby providing the driving force for blood to flow into collectionchamber 908. However, blood entering collection chamber 908 cannot moveinto vacuum chamber 907 due to the presence of gas-permeable membrane935 that is present at the opposing end of piercing member 912, whichconnects the piercing member to collection chamber 908. Accordingly, theblood that is drawn into device 900 remains and can be collected withincollection chamber 908, without contaminating vacuum chamber 907 orfirst module 905. In some embodiments, a removable cap and needleassembly, which may contain plate 932 and needles 930 (for example,microneedles), can be removed and disposed, then replaced with a closedcap for transportation and/or storage (not shown). The cap could beremoved prior to placing the device 900 in an analysis machine, forexample.

A different configuration is illustrated in FIG. 13C, in anotherembodiment of the invention. In this example, device 900 is positionedon skin 999 (shown sideways in this figure). First module 905 includesvacuum chamber 907, similar to the embodiment described above withrespect to FIG. 13B. For example, vacuum chamber 905 may be aVacutainer™ tube or a Vacuette™ tube, or another similar vacuum chamber.However, in this embodiment, the vacuum chamber is not positionedperpendicular with respect to the surface of the skin, as in FIGS. 13Aand 13B, but instead is positioned substantially parallel to the skinwhen device 900 is used. Applicator region 940 containing needles 930,such as microneedles, is positioned on the right side of device 900 asis shown in FIG. 13C, rather than on the bottom of the device as shownin FIGS. 13A and 13B, i.e., the device is depicted in a sidewaysorientation in FIG. 13C with skin 999 on the right of the device asshown in this figure. However, it should be understood that devices asdiscussed herein may work over a range of orientations, includinghorizontal, vertical, upside down, at an angle, etc. This feature isimportant since the device may be applied to any suitable location onthe body of a subject while the subject is in any suitable (orcomfortable) position, e.g., standing, sitting, lying down, etc., andthus, the device may be applied at any suitable angle necessary toaccess the skin of the subject at the desired location.

As with FIG. 13B, in FIG. 13C, first module 905 including a vacuumchamber 907 can be connected to second module 910. First module 905 alsoincludes a septum 902 for maintaining the reduced pressure inside vacuumchamber 907, and optionally cap 903 for protection. Cap 903 may includean opening 904 to allow the insertion of a piercing member 912 intoseptum 902. In some cases, cap 903 may be supplied as part of theVacutainer™ tube or a Vacuette™ tube, e.g., to hold a septum in placeprior to use.

Upon connection of first module 905 and second module 910, septum 902 offirst module 905 is penetrated by piercing member 912 from second module910. However, unlike in FIGS. 13A and 13B, connecting first module 905and second module 910 does not immediately result in the receiving ofblood by the device. Instead, piercing member 912, in this embodiment ahollow tube, is connected to a small chamber 914 which is blocked at oneend by pierceable surface 950. As long as pierceable surface 950 remainsintact, even when first module 905 is connected to second module 910such that septum 902 is pierced by piercing member 912, device 900 isstill able to maintain a reduced pressure within vacuum chamber 907,prior to use.

The body 919 of second module 910 may be formed out of any suitablematerial, for example, a polymer, rubber, or the like. Second module 910also includes a flexible concave member 920. In this embodiment,flexible concave member 920 has characteristics similar to thosepreviously described, e.g., flexible concave member 920 can adopt afirst configuration or a second configuration, although flexible concavemember 920 is not able to adopt a stable configuration in a positionmidway between the first configuration and the second configuration.Mechanically coupled to flexible concave member 920 is piercing member955. Piercing member 955 may be directly attached to flexible concavemember 920, or piercing member 955 may be positioned such that movementof flexible concave member 920 from a first configuration to a secondconfiguration causes piercing member 955 to move, as is illustrated inFIG. 13C. In this figure, as flexible concave member 920 moves from thefirst position to the second configuration, flexible concave member 920pushes piercing member 955 downwards (i.e., to the right in FIG. 13C),which causes piercing member 955 to come into contact with pierceablesurface 950, causing pierceable surface 950 to be pierced or otherwisebe disrupted. Disruption of pierceable surface 950 thus allows fluidiccommunication with reduced pressure within vacuum chamber 907 to occur.

In the embodiment shown in FIG. 13C, device 900 also includes aretraction mechanism that is able to urge or move flexible concavemember 920 to move from the second configuration back to the firstconfiguration. The retraction mechanism may cause retraction of theflexible concave member away from the skin, and/or the retractionmechanism may be able to move the flexible concave member from thesecond configuration to the first configuration. For example, in somecases, the retraction mechanism may be designed only to cause retractionof the flexible concave member away from the skin, without being able toreturn the flexible concave member to the first configuration. In thisexample, the retraction mechanism takes the form of a spring 966, whichis positioned around activation member 924. When flexible concave member920 is moved from the first configuration to the second configuration,spring 966 is compressed, and the compressed spring subsequently triesto expand, thereby pushing flexible concave member 920 from the secondconfiguration back to the first configuration, thus illustrating aconfiguration in which the retraction mechanism is able to both retractthe flexible concave member away from the skin and return it to thefirst configuration. Spring 966 may be, in some embodiments, initiallypartially compressed, then addition force, e.g., caused by movingflexible concave member 920 from the first configuration to the secondconfiguration, may be used to further compress the spring, and/or to beable to cause subsequent configuration changes to occur, e.g., aspreviously discussed. In other embodiments, other retraction mechanismsmay be used in addition to or besides a spring, for example, acompressible foam.

In FIG. 13C, activation member 924 mechanically couples flexible concavemember 920 to needles 930 attached to plate 932. As previously noted,mechanical coupling is performed via activation members 924 in thisexample, although in other embodiments, other mechanical couplingsystems may be used. In this embodiment, as flexible concave member 920moves from the first configuration to the second configuration, therebypushing activation member 924 to the right in FIG. 13C, needles 930 arepushed downwardly (i.e., to the right in FIG. 13C) through applicatorregion 940, for insertion into the skin of a subject. After insertion,the activation member may be withdrawn due to mechanical action ofspring 966 or another retraction mechanism, withdrawing plate 932 andneedles 930 away from the skin (i.e., to the left in FIG. 13C), andthereby allowing blood to flow from the subject.

Flexible concave member 920 may be actuated using any suitable actuator,for example, buttons, dials, levers, sliders, or the like. In FIG. 13C,an example of an actuator having the form of a button that is pushed bya user is illustrated. In this figure, a button dome 960 is illustratedcovering activation member 963. The button dome may be made out of anysuitable material, e.g. a rubber or a polymer. By pushing button dome960, activation member 963 is pushed into flexible concave member 920,thereby causing flexible concave member 920 to move from the firstconfiguration to the second configuration, compressing spring 966 andpushing activation member 924 to the right to move plate 932 and needles930 into the skin of a subject.

Blood released from the skin of a subject, after insertion of needles930, may flow into applicator region 940 and into transfer channel 965.From transfer channel 965, the blood (or other received fluid) may flowinto collection chamber 908, positioned in this example at the top ofsecond module 910 in FIG. 13C covered by a cap 911. Cap 911 maysubsequently be removed, e.g., for access of blood or other fluid withincollection chamber 908. Transfer channel 968 fluidically connectscollection chamber 908 to a region surrounding flexible concave member920, which is in fluidic communication with vacuum chamber 907 throughthe piercing of pierceable surface 950 by piercing member 955 andpiercing member 912, as noted above. In some cases, fluidic access maybe facilitated by holes or other structures within flexible concavemember 920, as is indicated by holes 921 in FIG. 13C. Accordingly, bypiercing surface 950 using member 955, which is activated by themovement of flexible concave member 920 from a first configuration to asecond configuration (e.g., upon pushing of button 960, as noted above),a fluidic pathway is created from vacuum chamber 907 through piercingmember 912, pierceable surface 950, holes 921 in flexible concavesurface 920, through channel 968 to collection chamber 908, and fromcollection chamber 908 through channel 965 to applicator region 940.Thus, the reduced pressure from vacuum chamber 907 is able to urge ormove blood within applicator region 940 to move through channel 965 andinto collection chamber 908. In some cases, transfer channel 968 may beseparated from collection chamber 908, e.g., to prevent blood or otherbodily fluids from flowing through the rest of second module 910, usingan appropriate separator, such as a gas-permeable membrane, ahydrophilic membrane, a porous structure, or the like (not shown in FIG.13C).

A similar configuration is illustrated in FIG. 13D, in accordance withanother embodiment of the invention. Device 900 is positioned on thesurface of skin 999, and like the device shown in FIG. 13C, includesfirst module 905, comprising a Vacutainer™ tube or a Vacuette™ tube, orother suitable vacuum chamber, and second module 910 containing variousother components. In this example, however, first module 905 alsocontains collection chamber 908, and the routing in this device of bloodor other bodily fluids received from the skin of a subject is somewhatdifferent than the device shown in FIG. 13C. In this figure, collectionchamber 908 may have a shape that fits substantially inside vacuumchamber 907, and in certain embodiments, collection chamber 908 may alsobe removable from vacuum chamber 907, for instance, for analysis ofblood or other bodily fluids that are received from the subject. Inother embodiments, however, collection chamber 908 may not be easilyremovable from vacuum chamber 907.

It should be noted that in FIG. 13D, a septum is not used to maintainvacuum within vacuum chamber 907, and instead, the opening of vacuumchamber 907 of first module 905 is sealed using a combination ofcollection chamber 908 and pierceable surface 950. Thus, first module905 and second module 910 can be connected together to form device 900without releasing the reduced pressure within vacuum chamber 907.Pierceable surface 950, in this embodiment, can be pierced by piercingmember 955. Upon piercing of pierceable surface 950 by piercing member955, a fluidic communication pathway is formed from vacuum chamber 907,through channel 967, to applicator region 940.

The device in FIG. 13D also requires a button to be pushed to activatethe device. As previously discussed, other actuators may also be used toactivate the device, including dials, levers, sliders, or the like. Inthis example, button dome 960 may be pushed to move activation member963, causing it to push flexible concave member 920 from a firstconfiguration to a second configuration. Flexible concave member 920cannot adopt a stable configuration in a position midway between thefirst configuration and the second configuration. In FIG. 13D, flexibleconcave member 920 is illustrated in the first configuration. Whenflexible concave member 920 is moved from the first configuration to asecond configuration, flexible concave member 920 moves activationmember 924 (i.e., to the right in FIG. 13D), which causes movement ofplate 932 and needles 930 immobilized with respect to plate 932. Inother embodiments, other substance transfer components may be usedinstead of and/or in addition to needles 930. Needles 930 are then movedthrough applicator region 940 and can be inserted into the skin of asubject. Optionally, a retractor mechanism (not shown) may be used tomove flexible concave member 920 away from the skin, and/or to returnflexible concave member 920 from the second configuration to the firstconfiguration, moving activator rods 924 away from the skin (i.e., tothe left in FIG. 13D), withdrawing needles 930 from the skin of thesubject.

The insertion of needles into the skin of the subject may cause blood orother bodily fluids to be released into applicator region 940. Thefluids may then flow through channels 967 into collection chamber 908,for example, due to action of the vacuum from second chamber 907, whichis released when activation member 963 pushes piercing member 955downwardly into pierceable surface 950, thereby causing a fluidicconnection with vacuum chamber 907 to be formed with applicator region940. In some cases, collection chamber 908 may be separate from vacuumchamber 907 using a gas-permeable membrane, a hydrophilic membrane, aporous structure or the like (not shown).

A somewhat different configuration is illustrated in FIG. 13E. In thisexample, device 900 may be prepackaged with an internal vacuum, e.g.,within chamber 971. The vacuum may initially be charged in the deviceusing a septum (970) during manufacture. In addition, device 900 doesnot include separate modules in this example. The body 919 of device 900may be formed out of any suitable material, for example, a polymer,rubber, or the like.

Vacuum or reduced pressure is introduced in the embodiment shown in FIG.13E via port 970, which is located on one side of device 900. A vacuummay be present within first chamber 971 of the device, which isseparated from collection chamber 908 of the device due to the presenceof pierceable surface 950 dividing the two chambers. Pierceable surface950 may be pierced using one or more piercing members 955 which areconnected, either directly or indirectly, to a button on top of device900 that can be pushed by a user to activate device 900. For example,the button may be connected to an actuator rod to cause piercing member955 to pierce pierceable surface 950. Thus, when button 960 is pushed,piercing members 955 are inserted into pierceable surface 950 to createfluidic communication between first chamber 971 and collection chamber908.

In addition, by pushing button 960, activation member 963 is also moved,which in turn pushes on activation plate 961 and flexible concave member920, causing it to move from a first configuration to a secondconfiguration. Flexible concave member 920 cannot adopt a stableconfiguration in a position midway between the first configuration andthe second configuration, and thus moves into a second configuration,which pushes activation member 924 downwardly, which in turn causesplate 932 and needles 930 on plate 932 to also move downwardly throughapplicator region 940 and into the skin of a subject to which the deviceis applied. Optionally, device 900 may also include a retractionmechanism such as those previously discussed, although such a retractionmechanism is not illustrated in FIG. 13E.

Blood or other bodily fluids entering applicator region 940 can enterchannel 967 under influence of the reduce pressure from the reducedpressure in chamber 971, which is in fluidic communication withcollection chamber 908. Thus, blood or other bodily fluids may flow fromapplicator region 940, through channel 967, and into collection chamber908 to be collected therein.

Also shown in FIG. 13E is an optional support tube 980, shown here indashed outline. Optional support tube 980 may be used to protectapplicator region 940 of the device prior to use, or simply to allow thedevice to be placed on a surface before or after use. In some cases,support tube 980 may be of a size similar to a Vacutainer™ tube or aVacuette™ tube, which may be used to interface device 900 withcommercially-available phlebotomy equipment able to process or handleVacutainer™ or Vacuette™ tubes. In some embodiments, support tube 980may be attached and cap 960 may be removed in order to allow a samplecontained within the device to be processed on automated diagnosticequipment designed for use with Vacutainer™ and/or Vacuette™ tubes.

In some cases, the device may be constructed and arranged to interfacewith various test strips, cartridges, or cuvettes, including those thatare commercially available. Non-limiting examples of such systemsinclude i-STAT Cartridges, Hemocue cuvettes, Hemopoint cuvettes,Novobiomed test strips, Cholestech cartridges, or the like. For example,in one set of embodiments, the device may be constructed and arrangedsuch that blood or other bodily fluids received from the skin of asubject may be delivered to a cartridge or a cuvette, e.g., forsubsequent insertion into a meter, e.g., into an i-STAT Cartridge. Asanother example, blood received from a subject as is discussed hereinmay be placed on a Hemocue or Hemopoint cuvette (e.g., manually, or byinsertion of the cuvette into the device as is discussed herein, similarin manner to a test strip), or a test strip such as a test strip used ina Novobiomed handheld device.

Devices of the invention can provide significant advantage according tosome embodiments. For example, triggering mechanisms able to movesubstance transfer components or skin insertion objects in short timeperiods, and/or at high velocities, and/or with high forces, and/or withhigh pressure, and/or drive relatively short skin insertion objects suchas microinsertion objects or microneedles relatively deeply into theskin and/or through the skin, and/or any combination of the above canprovide significant advantage. In some embodiments, these features canprovide better control of substance delivery or receiving. Bettermechanical stability can be provided in some cases by shorter skininsertion objects (e.g., bending and/or buckling can be avoided) andrelatively shorter skin insertion objects, designed to be drivenrelatively completely (for example, through nearly all of their entirelength) into the skin may offer better control of penetration in someembodiments. If better control of penetration can be achieved, betterdelivery or receiving can also be achieved in some cases, for example,resulting in less pain or essentially painless deployment.

Moreover, if skin insertion objects are used to deliver a substance suchas a pharmaceutical composition into or through the skin, more precisedelivery can be provided, according to certain embodiments. With better,precise control over depth of insertion of the skin insertion objects(e.g., by using devices designed to insert the skin insertion objectsessentially fully), and/or the skin insertion objects contain and/or arecoated with a pharmaceutical composition, then more control exists overthe amount of pharmaceutical substance inserted into the skin by theskin insertion objects, in some embodiments. Furthermore, quick and/orhigh velocity, and/or high force and/or pressure application of skininsertion objects to the skin may in certain embodiments result in lowerpain or painless deployment.

According to one set of embodiments, many devices as discussed hereinuse various techniques for delivering and/or receiving fluid, forexample, in connection with fluid transporters, substance transfercomponents, skin insertion objects, microinsertion objects, or the like.For example, one or more needles and/or microneedles, a hygroscopicagent, a cutter or other piercing element, an electrically-assistedsystem, or the like may be used in conjunction with a snap dome or otherdevice as described above. Additional examples of such techniques aredescribed herein and/or in the applications incorporated herein. It isto be understood that, generally, fluids may be delivered and/orreceived in a variety of ways, and various systems and methods fordelivering and/or receiving fluid from the skin are discussed belowand/or in the applications incorporated herein. In some embodiments, forexample, techniques for piercing or altering the surface of the skin totransport a fluid are discussed, for example, using a needle such as ahypodermic needle or microneedles, chemicals applied to the skin (e.g.,penetration enhancers), jet injectors or other techniques such as thosediscussed below, etc.

As an example, in one embodiment, a needle such as a hypodermic needlecan be used to deliver and/or receive fluid to or from the skin.Hypodermic needles are well-known to those of ordinary skill in the art,and can be obtained commercially with a range of needle gauges. Forexample, the needle may be in the 20-30 gauge range, or the needle maybe 32 gauge, 33 gauge, 34 gauge, etc.

If needles are present, the needles may be of any suitable size andlength, and may be solid or hollow. The needles may have any suitablecross-section (e.g., perpendicular to the direction of penetration), forexample, circular, square, oval, elliptical, rectangular, roundedrectangle, triangular, polygonal, hexagonal, irregular, etc. Forexample, the needle may have a length of less than about 5 mm, less thanabout 4 mm, less than about 3 mm, less than about 2 mm, less than about1 mm, less than about 800 micrometers, less than 600 micrometers, lessthan 500 micrometers, less than 400 micrometers, less than about 300micrometers, less than about 200 micrometers, less than about 175micrometers, less than about 150 micrometers, less than about 125micrometers, less than about 100 micrometers, less than about 75micrometers, less than about 50 micrometers, etc. The needle may alsohave a largest cross-sectional dimension of less than about 5 mm, lessthan about 4 mm, less than about 3 mm, less than about 2 mm, less thanabout 1 mm, less than about 800 micrometers, less than 600 micrometers,less than 500 micrometers, less than 400 micrometers, less than about300 micrometers, less than about 200 micrometers, less than about 175micrometers, less than about 150 micrometers, less than about 125micrometers, less than about 100 micrometers, less than about 75micrometers, less than about 50 micrometers, etc. For example, in oneembodiment, the needle may have a rectangular cross section havingdimensions of 175 micrometers by 50 micrometers. In one set ofembodiments, the needle may have an aspect ratio of length to largestcross-sectional dimension of at least about 2:1, at least about 3:1, atleast about 4:1, at least 5:1, at least about 7:1, at least about 10:1,at least about 15:1, at least about 20:1, at least about 25:1, at leastabout 30:1, etc.

In one embodiment, the needle is a microneedle. As an example,microneedles such as those disclosed in U.S. Pat. No. 6,334,856, issuedJan. 1, 2002, entitled “Microneedle Devices and Methods of Manufactureand Use Thereof,” by Allen, et al., may be used to deliver and/orreceive fluids or other materials to or from a subject. The microneedlesmay be hollow or solid, and may be formed from any suitable material,e.g., metals, ceramics, semiconductors, organics, polymers, and/orcomposites. Examples include, but are not limited to, pharmaceuticalgrade stainless steel, titanium, nickel, iron, gold, tin, chromium,copper, alloys of these or other metals, silicon, silicon dioxide, andpolymers, including polymers of hydroxy acids such as lactic acid andglycolic acid polylactide, polyglycolide, polylactide-co-glycolide, andcopolymers with polyethylene glycol, polyanhydrides, polyorthoesters,polyurethanes, polybutyric acid, polyvaleric acid,polylactide-co-caprolactone, polycarbonate, polymethacrylic acid,polyethylenevinyl acetate, polytetrafluorethylene, polymethylmethacrylate, polyacrylic acid, or polyesters. In some cases, more thanone microneedle may be used. For example, arrays of microneedles may beused, and the microneedles may be arranged in the array in any suitableconfiguration, e.g., periodic, random, etc. In some cases, the array mayhave 3 or more, 4 or more, 5 or more, 6 or more, 10 or more, 15 or more,20 or more, 35 or more, 50 or more, 100 or more, or any other suitablenumber of microneedles. In some embodiments, the device may have atleast 3 but no more than 5 needles or microneedles (or other substancetransfer components), at least 6 but no more than 10 needles ormicroneedles, or at least 11 but no more than 20 needles ormicroneedles. Typically, a microneedle will have an averagecross-sectional dimension (e.g., diameter) of less than about a micron.It should be understood that references to “needle” or “microneedle” asdiscussed herein are by way of example and ease of presentation only,and that in other embodiments, more than one needle and/or microneedlemay be present in any of the descriptions herein.

Those of ordinary skill in the art can arrange needles relative to theskin for these purposes including, in one embodiment, introducingneedles into the skin at an angle, relative to the skin's surface, otherthan 90°, i.e., to introduce a needle or needles into the skin in aslanting fashion so as to limit the depth of penetration. In anotherembodiment, however, the needles may enter the skin at approximately90°.

In some cases, the microneedles may be present in an array selected suchthat the density of microneedles within the array is between about 0.5needles/mm² and about 10 needles/mm², and in some cases, the density maybe between about 0.6 needles/mm² and about 5 needles/mm², between about0.8 needles/mm² and about 3 needles/mm², between about 1 needles/mm² andabout 2.5 needles/mm², or the like. In some cases, the needles may bepositioned within the array such that no two needles are closer thanabout 1 mm, about 0.9 mm, about 0.8 mm, about 0.7 mm, about 0.6 mm,about 0.5 mm, about 0.4 mm, about 0.3 mm, about 0.2 mm, about 0.1 mm,about 0.05 mm, about 0.03 mm, about 0.01 mm, etc.

In another set of embodiments, the microneedles may be chosen such thatthe area of the microneedles (determined by determining the area ofpenetration or perforation on the surface of the skin of the subject bythe microneedles) allows for adequate flow of fluid to or from thesubject. The microneedles may be chosen to have smaller or larger areas(or smaller or large diameters), so long as the area of contact for themicroneedles to the skin is sufficient to allow adequate blood flow fromthe subject to the device. For example, in certain embodiments, themicroneedles may be selected to have a combined skin-penetration area ofat least about 500 nm², at least about 1,000 nm², at least about 3,000nm², at least about 10,000 nm², at least about 30,000 nm², at leastabout 100,000 nm², at least about 300,000 nm², at least about 1microns², at least about 3 microns², at least about 10 microns², atleast about 30 microns², at least about 100 microns², at least about 300microns², at least about 500 microns², at least about 1,000 microns², atleast about 2,000 microns², at least about 2,500 microns², at leastabout 3,000 microns², at least about 5,000 microns², at least about8,000 microns², at least about 10,000 microns², at least about 35,000microns², at least about 100,000 microns², etc., depending on theapplication.

The microneedles may have any suitable length, and the length may be, insome cases, dependent on the application. For example, needles designedto only penetrate the epidermis may be shorter than needles designed toalso penetrate into the dermis, or to extend beneath the dermis or theskin. In certain embodiments, the microneedles may have a maximumpenetration into the skin of no more than about 3 mm, no more than about2 mm, no more than about 1.75 mm, no more than about 1.5 mm, no morethan about 1.25 mm, no more than about 1 mm, no more than about 900micron, no more than about 800 microns, no more than about 750 microns,no more than about 600 microns, no more than about 500 microns, no morethan about 400 microns, no more than about 300 microns, no more thanabout 100 microns, no more than about 175 micrometers, no more thanabout 150 micrometers, no more than about 125 micrometers, no more thanabout 100 micrometers, no more than about 75 micrometers, no more thanabout 50 micrometers, etc. In certain embodiments, the needle may beselected so as to have a maximum penetration into the skin of at leastabout 50 micrometers, at least about 100 micrometers, at least about 300micrometers, at least about 500 micrometers, at least about 1 mm, atleast about 2 mm, at least about 3 mm, etc.

In one embodiment, the fluid is delivered and/or received manually,e.g., by manipulating a plunger on a syringe. In another embodiment, thefluid can be delivered and/or received from the skin mechanically orautomatically, e.g., using a piston pump or the like. Fluid may also bereceived using vacuums such as those discussed herein. For example,vacuum may be applied to a conduit, such as a needle, in fluidiccommunication with a bodily fluid in order to draw up at least a portionof the fluid from the skin. In yet another embodiment, fluid is receivedusing capillary action (e.g., using a microfluidic channel or hypodermicneedle having a suitably narrow inner diameter). In still anotherembodiment, pressure may be applied to force fluid out of the needle.

As still another example, pressurized fluids may be used to deliverfluids or other materials into the skin, for instance, using a jetinjector or a “hypospray.” Typically, such devices produce ahigh-pressure “jet” of liquid or powder (e.g., a biocompatible liquid,such as saline) that drives material into the skin, and the depth ofpenetration may be controlled, for instance, by controlling the pressureof the jet. The pressure may come from any suitable source, e.g., astandard gas cylinder or a gas cartridge. A non-limiting example of sucha device can be seen in U.S. Pat. No. 4,103,684, issued Aug. 1, 1978,entitled “Hydraulically Powered Hypodermic Injector with Adapters forReducing and Increasing Fluid Injection Force,” by Ismach.

In some embodiments, fluid may be received using a hygroscopic agentapplied to the surface of the skin, or proximate the skin. For example,a device as described herein may contain a hygroscopic agent. In somecases, pressure may be applied to drive the hygroscopic agent into theskin. Hygroscopic agents typically are able to attract water from thesurrounding environment, for instance, through absorption or adsorption.Non-limiting examples of hygroscopic agents include sugar, honey,glycerol, ethanol, methanol, sulfuric acid, methamphetamine, iodine,many chloride and hydroxide salts, and a variety of other substances.Other examples include, but are not limited to, zinc chloride, calciumchloride, potassium hydroxide, or sodium hydroxide. In some cases, asuitable hygroscopic agent may be chosen based on its physical orreactive properties, e.g., inertness or biocompatibility towards theskin of the subject, depending on the application.

In some embodiments, the device may comprise a cutter able to cut orpierce the surface of the skin. The cutter may comprise any mechanismable to create a path through which fluids may be delivered and/orreceived from the skin. For example, the cutter may comprise ahypodermic needle, a blade (e.g., a knife blade, a serrated blade,etc.), a piercing element (e.g., a lancet or a solid or a hollowneedle), or the like, which can be applied to the skin to create asuitable conduit for the delivery and/or receiving of fluid from theskin. In one embodiment, a cutter is used to create such a pathway andremoved, then fluid may be delivered and/or received via this pathway.In another embodiment, the cutter remains in place within the skin, andfluid may be delivered and/or received through a conduit within thecutter.

In some embodiments, fluid may be received using an electric charge. Forexample, reverse iontophoresis may be used. Without wishing to be boundby any theory, reverse iontophoresis uses a small electric current todrive charged and highly polar compounds across the skin. Since the skinis negatively charged at physiologic pH, it acts as a permselectivemembrane to cations, and the passage of counterions across the skininduces an electroosmotic solvent flow that may carry neutral moleculesin the anode-to-cathode direction. Components in the solvent flow may beanalyzed as described elsewhere herein. In some instances, a reverseiontophoresis apparatus may comprise an anode cell and a cathode cell,each in contact with the skin. The anode cell may be filled, forexample, with an aqueous buffer solution (i.e., aqueous Tris buffer)having a pH greater than 4 and an electrolyte (i.e. sodium chloride).The cathode cell can be filled with aqueous buffer. As one example, afirst electrode (e.g., an anode) can be inserted into the anode cell anda second electrode (e.g., a cathode) can be inserted in the cathodecell. In some embodiments, the electrodes are not in direct contact withthe skin.

A current may be applied to induce reverse iontophoresis, therebyreceiving a fluid from the skin. The current applied may be, forexample, greater than 0.01 mA, greater than 0.3 mA, greater than 0.1 mA,greater than 0.3 mA, greater than 0.5 mA, or greater than 1 mA. Itshould be understood that currents outside these ranges may be used aswell. The current may be applied for a set period of time. For example,the current may be applied for greater than 30 seconds, greater than 1minute, greater than 5 minutes, greater than 30 minutes, greater than 1hour, greater than 2 hours, or greater than 5 hours. It should beunderstood that times outside these ranges may be used as well.

In one set of embodiments, the device may comprise an apparatus forablating the skin. Without wishing to be bound by any theory, it isbelieved that ablation comprises removing a microscopic patch of stratumcorneum (i.e., ablation forms a micropore), thus allowing access tobodily fluids. In some cases, thermal, radiofrequency, and/or laserenergy may be used for ablation. In some instances, thermal ablation maybe applied using a heating element.

Radiofrequency ablation may be carried out using a frequency and energycapable of heating water and/or tissue. A laser may also be used toirradiate a location on the skin to remove a portion. In someembodiments, the heat may be applied in pulses such that a steeptemperature gradient exists essentially perpendicular to the surface ofthe skin. For example, a temperature of at least 100° C., at least 200°C., at least 300° C., or at least 400° C. may be applied for less than 1second, less than 0.1 seconds, less than 0.01 seconds, less than 0.005seconds, or less than 0.001 seconds.

In some embodiments, the device may comprise a mechanism for taking asolid sample of tissue. For example, a solid tissue sample may beacquired by methods such as scraping the skin or cutting out a portion.Scraping may comprise a reciprocating action whereby an instrument isscraped along the surface of the skin in two or more directions.Scraping can also be accomplished by a rotating action, for exampleparallel to the surface of the skin and in one direction (i.e., with aroller drum) or parallel to the surface of the skin and in a circularmanner (i.e., with a drilling instrument). A cutting mechanism maycomprise a blade capable of making one or more incisions and a mechanismfor removing a portion of tissue (i.e., by suction or mechanicallypicking up) or may use a pincer mechanism for cutting out a portion oftissue. A cutting mechanism may also function by a coring action. Forexample, a hollow cylindrical device can be penetrated into the skinsuch that a cylindrical core of tissue may be removed. A solid samplemay be analyzed directly or may be liquefied prior to analysis.Liquefaction can comprise treatment with organic solvents, enzymaticsolutions, surfactants, etc.

The device may also contain, in some embodiments, a vacuum source. Insome cases, the vacuum source is one that is self-contained within thedevice, i.e., the device need not be connected to an external vacuumsource (e.g., a house vacuum) during use of the device to receive bloodfrom the skin. For example, in one set of embodiments, the vacuum sourcemay include a vacuum chamber having a pressure less than atmosphericpressure before blood (or other fluid) is received into the device,i.e., the vacuum chamber is at a “negative pressure” (that is, negativerelative to atmospheric pressure) or a “vacuum pressure” (or just havinga “vacuum”). For example, the vacuum in the vacuum chamber may be atleast about 50 mmHg, at least about 100 mmHg, at least about 150 mmHg,at least about 200 mmHg, at least about 250 mmHg, at least about 300mmHg, at least about 350 mmHg, at least about 400 mmHg, at least about450 mmHg, at least about 500 mmHg, at least 550 mmHg, at least 600 mmHg,at least 650 mmHg, at least about 700 mmHg, or at least about 750 mmHg,i.e., below atmospheric pressure. Thus, the pressure within the vacuumis at a “reduced pressure” relative to atmospheric pressure, e.g., thevacuum chamber is a reduced pressure chamber. However, in otherembodiments, it should be understood that other pressures may be usedand/or that different methods may be used to produce other pressures(greater than or less than atmospheric pressure). As non-limitingexamples, an external vacuum or a mechanical device may be used as thevacuum source; various additional examples are discussed in detailherein.

As a specific, non-limiting example, in one embodiment, a device may beused to receive fluid without an external power and/or a vacuum source.Examples of such devices include skin patches, strips, tapes, bandages,or the like. For instance, a skin patch may be contacted with the skinof a subject, and a vacuum created through a change in shape of aportion of the skin patch or other device (e.g., using a shape memorypolymer), which may be used to deliver and/or receive fluid from theskin. As a specific example, a shape memory polymer may be shaped to beflat at a first temperature (e.g., room temperature) but curved at asecond temperature (e.g., body temperature), and when applied to theskin, the shape memory polymer may alter from a flat shape to a curvedshape, thereby creating a vacuum. As another example, a mechanicaldevice may be used to create the vacuum, For example, springs, coils,expanding foam (e.g., from a compressed state), a shape memory polymer,shape memory metal, or the like may be stored in a compressed or woundreleased upon application to a subject, then released (e.g., unwinding,uncompressing, etc.), to mechanically create the vacuum.

Thus, in some cases, the device is “pre-packaged” with a suitable vacuumsource (e.g., a pre-evacuated vacuum chamber); for instance, in oneembodiment, the device may be applied to the skin and activated in somefashion to create and/or access the vacuum source. In yet anotherexample, a chemical reaction may be used to create a vacuum, e.g., areaction in which a gas is produced, which can be harnessed to providethe mechanical force to create a vacuum. In still another example, acomponent of the device may be able to create a vacuum in the absence ofmechanical force. In another example, the device may include aself-contained vacuum actuator, for example, chemical reactants, adeformable structure, a spring, a piston, etc.

In one set of embodiments, the device may be able to create a pressuredifferential (e.g. a vacuum). The pressure differential may be createdby a pressure regulator. As used here, “pressure regulator” is apressure controller component or system able to create a pressuredifferential between two or more locations. The pressure differentialshould be at least sufficient to urge or move the movement of fluid orother material in accordance with various embodiments of the inventionas discussed herein, and the absolute pressures at the two or morelocations are not important so long as their differential isappropriate, and their absolute values are reasonable for the purposesdiscussed herein. For example, the pressure regulator may produce apressure higher than atmospheric pressure in one location, relative to alower pressure at another location (atmospheric pressure or some otherpressure), where the differential between the pressures is sufficient tourge or move fluid in accordance with the invention. In another example,the regulator or controller will involve a pressure lower thanatmospheric pressure (a vacuum) in one location, and a higher pressureat another location(s) (atmospheric pressure or a different pressure)where the differential between the pressures is sufficient to urge ormove fluid in accordance with the invention. Wherever “vacuum” or“pressure” is used herein, in association with a pressure regulator orpressure differential of the invention, it should be understood that theopposite can be implemented as well, as would be understood by those ofordinary skill in the art, i.e., a vacuum chamber can be replaced inmany instances with a pressure chamber, for creating a pressuredifferential suitable for urging the movement of fluid or othermaterial.

The pressure regulator may be an external source of vacuum (e.g. a lab,clinic, hospital, etc., house vacuum line or external vacuum pump), amechanical device, a vacuum chamber, pre-packaged vacuum chamber, or thelike. In some cases, vacuum may be created manually, e.g., bymanipulating a syringe pump, a plunger, or the like, or the low pressuremay be created mechanically or automatically, e.g., using a piston pump,a syringe, a bulb, a Venturi tube, manual (mouth) suction, etc., or thelike. Vacuum chambers can be used in some embodiments, where the devicecontains, e.g., regions in which a vacuum exits or can be created (e.g.a variable volume chamber, a change in volume of which will affectvacuum or pressure). A vacuum chamber can include pre-evacuated (i.e.,pre-packaged) chambers or regions, and/or self-contained actuators.

A “self-contained” vacuum (or pressure) regulator means one that isassociated with (e.g., on or within) the device, e.g. one that definesan integral part of the device, or is a separate component constructedand arranged to be specifically connectable to the particular device toform a pressure differential (i.e., not a connection to an externalsource of vacuum such as a hospital's, clinic's, or lab's house vacuumline, or a vacuum pump suitable for very general use). In someembodiments, the self-contained vacuum source may be actuated in somefashion to create a vacuum within the device. For instance, theself-contained vacuum source may include a piston, a syringe, amechanical device such as a vacuum pump able to create a vacuum withinthe device, and/or chemicals or other reactants that can react toincrease or decrease pressure which, with the assistance of mechanicalor other means driven by the reaction, can form a pressure differentialassociated with a pressure regulator. Chemical reaction can also drivemechanical actuation with or without a change in pressure based on thechemical reaction itself. A self-contained vacuum source can alsoinclude an expandable foam, a shape memory material, or the like.

One category of self-contained vacuum or pressure regulators of theinvention includes self-contained assisted regulators. These areregulators that, upon actuation (e.g., the push of a button, orautomatic actuation upon, e.g., removal from a package or urging adevice against the skin), a vacuum or pressure associated with thedevice is formed where the force that pressurizes or evacuates a chamberis not the same as the actuation force. Examples of self-containedassisted regulators include chambers evacuated by expansion driven by aspring triggered by actuation, release of a shape-memory material orexpandable material upon actuation, initiation of a chemical reactionupon actuation, or the like.

Another category of self-contained vacuum or pressure regulators of theinvention are devices that are not necessarily pre-packaged withpressure or vacuum, but which can be pressurized or evacuated, e.g. by asubject, health care professional at a hospital or clinic prior to use,e.g. by connecting a chamber of the device to a source of vacuum orpressure. For example, the subject, or another person, may actuate thedevice to create a pressure or vacuum within the device, for example,immediately prior to use of the device.

The vacuum or pressure regulator may be a “pre-packaged” pressure orvacuum chamber in the device when used (i.e., the device can be providedready for use by a subject or practitioner with an evacuated region onor in the device, without the need for any actuation to form the initialvacuum). A pre-packaged pressure or vacuum chamber regulator can, e.g.,be a region evacuated (relative to atmospheric pressure) uponmanufacture and/or at some point prior to the point at which it is usedby a subject or practitioner. For example, a chamber is evacuated uponmanufacture, or after manufacture but before delivery of the device tothe user, e.g. the clinician or subject. For instance, in someembodiments, the device contains a vacuum chamber having a vacuum of atleast about 50 mmHg, at least about 100 mmHg, at least about 150 mmHg,at least about 200 mmHg, at least about 250 mmHg, at least about 300mmHg, at least about 350 mmHg, at least about 400 mmHg, at least about450 mmHg, at least about 500 mmHg, at least about 550 mmHg, at leastabout 600 mmHg, at least about 650 mmHg, at least about 700 mmHg, or atleast about 750 mmHg below atmospheric pressure.

In one set of embodiments, a device of the present invention may nothave an external power and/or a vacuum source. In some cases, the deviceis “pre-loaded” with a suitable vacuum source; for instance, in oneembodiment, the device may be applied to the skin and activated in somefashion to create and/or access the vacuum source. As one example, adevice of the present invention may be contacted with the skin of asubject, and a vacuum created through a change in shape of a portion ofthe device (e.g., using a shape memory polymer), or the device maycontain one or more sealed, self-contained vacuum chambers, where a sealis punctured in some manner to create a vacuum. For instance, uponpuncturing the seal, a vacuum chamber may be in fluidic communicationwith a needle, which can be used to move the skin towards the device,receive fluid from the skin, or the like.

As another example, a shape memory polymer may be shaped to be flat at afirst temperature (e.g., room temperature) but curved at a secondtemperature (e.g., body temperature), and when applied to the skin, theshape memory polymer may alter from a flat shape to a curved shape,thereby creating a vacuum. As yet another example, a mechanical devicemay be used to create the vacuum, For example, springs, coils, expandingfoam (e.g., from a compressed state), a shape memory polymer, shapememory metal, or the like may be stored in a compressed or woundreleased upon application to a subject, then released (e.g., unwinding,uncompressing, etc.), to mechanically create the vacuum. Non-limitingexamples of shape-memory polymers and metals include Nitinol,compositions of oligo(epsilon-caprolactone)diol and crystallizableoligo(rho-dioxanone)diol, or compositions ofoligo(epsilon-caprolactone)dimethacrylate and n-butyl acrylate.

In yet another example, a chemical reaction may be used to create avacuum, e.g., a reaction in which a gas is produced, which can beharnessed to provide the mechanical force to create a vacuum. In someembodiments, the device may be used to create a vacuum automatically,once activated, without any external control by a user.

In one set of embodiments, the device contains a vacuum chamber that isalso used as a storage chamber to receive blood or other fluid receivedfrom the subject into the device. For instance, blood received from asubject through or via the substance transfer component may enter thevacuum chamber due to its negative pressure (i.e., because the chamberhas an internal pressure less than atmospheric pressure), and optionallystored in the vacuum chamber for later use. A non-limiting example isillustrated in FIG. 3. In this figure, device 600 contains vacuumchamber 610, which is connected to substance transfer component 620(which may be, e.g., one or more microneedles). Upon activation ofvacuum chamber 610 (e.g., using actuator 660, as discussed below),vacuum chamber 610 may be put into fluidic communication with substancetransfer component 620. Substance transfer component 620 may accordinglycause negative pressure to be applied to the skin of the subject, forinstance, due to the internal pressure within vacuum chamber 610. Fluid(e.g., blood) exciting the skin via substance transfer component 620 mayaccordingly be drawn into the device and into vacuum chamber 610, e.g.,through conduit 612. The fluid collected by the device can then beanalyzed within the device or removed from the device for analysis,storage, etc.

In another set of embodiments, however, the device may include separatevacuum chambers and storage chambers (e.g., chambers to store fluid suchas blood from the subject). The vacuum chamber and storage chambers maybe in fluid communication, and may have any suitable arrangement. Insome embodiments, the vacuum from the vacuum chamber may be used, atleast in part, to receive fluid from the skin, which is then directedinto a storage chamber, e.g., for later analysis or use, for example, asdiscussed below. As an example, blood may be received into the device,flowing towards a vacuum chamber, but the fluid may be prevented fromentering the vacuum chamber. For instance, in certain embodiments, amaterial permeable to gas but not to a liquid such as blood may be used.For example, the material may be a membrane such as a hydrophilic orhydrophobic membrane having a suitable porosity, a porous structure, aporous ceramic frit, a dissolvable interface (e.g., formed from a saltor a polymer, etc.), or the like.

One non-limiting example is illustrated in FIG. 4. In this figure,device 600 contains vacuum chamber 610 and storage chamber 615. Vacuumchamber 610 can be put in fluidic communication with storage chamber 615via conduit 612, which contains material 614. Material 614 may be anymaterial permeable to gas but not to a liquid in this example, e.g.,material 614 may be a membrane such as a hydrophilic membrane or ahydrophobic membrane that has a porosity that allows gas exchange tooccur but does not allow the passage of blood from the subject. Whendevice 600 is actuated using actuator 660, blood (or other fluid) flowsthrough substance transfer component 620 via conduit 661 into collectionchamber 615 because of the internal vacuum pressure from vacuum chamber610, which is not completely impeded by material 614 since it ispermeable to gases. However, because of material 614, blood (or othersuitable bodily fluid) is prevented from entering vacuum chamber 610,and instead remains in storage chamber 615, e.g., for later analysis oruse.

In some embodiments, the flow of blood (or other fluid) into the storagechamber may be controlled using a flow controller. The flow controllermay be manually and/or automatically controlled to control the flow ofblood. The flow controller may activate or deactivate when a certainamount or volume of fluid has entered the storage chamber in certaincases. For instance, the flow controller may stop blood flow after apredetermined amount or volume of blood has entered the storage chamber,and/or the flow controller may be able to control the internal pressureof the storage chamber, e.g., to a specific level, such as apredetermined level. Examples of suitable flow controllers for thedevice include, but are not limited to, a membrane, a valve, adissolvable interface, a gate, or the like.

One non-limiting example of a flow controller is now illustrated withreference to FIG. 5. In this example figure, device 600 includes avacuum chamber 610 and a storage chamber 615. Fluid entering device 600via substance transfer component 620 is prevented from entering storagechamber 615 due to flow controller 645 present within conduit 611.However, under suitable conditions, flow controller 645 may be opened,thereby allowing at least some fluid to enter storage chamber 615. Insome cases, for instance, storage chamber 615 also contains at least apartial vacuum, although this vacuum may be greater or less than thepressure within chamber 610. In other embodiments, flow controller 645may initially be open, or be externally controllable (e.g., via anactuator), or the like. In some cases, the flow controller may controlthe flow of fluid into the device such that, after collection, at leastsome vacuum is still present in the device.

Thus, in some cases, the device may be constructed and arranged toreproducibly obtain from the subject a controlled amount of fluid, e.g.,a controlled amount or volume of blood. The amount of fluid reproduciblyobtained from the subject may be controlled, for example, using flowcontrollers, materials permeable to gas but not to liquids, membranes,valves, pumps, gates, microfluidic systems, or the like, as discussedherein. In particular, it should be noted that the volume of blood orother fluid obtained from the subject need not be strictly a function ofthe initial vacuum pressure or volume within the device. For example, aflow controller may initially be opened (e.g., manually, automatically,electronically, etc.) to allow fluid to begin entering the device; andwhen a predetermined condition is reached (e.g., when a certain volumeor amount of blood has entered the device), the flow controller may beclosed at that point, even if some vacuum pressure remains within thedevice. In some cases, this control of fluid allows the amount of fluidreproducibly obtained from the subject to be controlled to a greatextent. For example, in one set of embodiments, the amount of fluidreceived from the subject may be controlled to be less than about 1 ml,may be less than about 300 microliters, less than about 100 microliters,less than about 30 microliters, less than about 10 microliters, lessthan about 3 microliters, less than about 1 microliter, etc.

Further examples of various embodiments of the invention are illustratedin FIGS. 6 and 8. In FIG. 6, device 500 is illustrated. In this example,device 500 includes a deployment actuator 501, an adhesive 502 foradhesion of the device to the skin, and a substance transfer componentsystem 503. In this figure, substance transfer component system 503includes a plurality of microneedles 505, although other substancetransfer components as discussed herein may also be used. Microneedles505 are contained within recess 508. Also shown in FIG. 6 is vacuumchamber 513 which, in this example, is self-contained within device 500.Vacuum chamber 513 is in fluidic communication with recess 508 viachannel 511, for example, as controlled by a controller or an actuator.Actuator 560 is shown at the top of device 500. Actuator 560 may be, forexample, a button, switch, slider, dial, etc. and may cause microneedles505 to move towards the skin when the device is placed on the skin. Forexample, the microneedles may be moved mechanically (e.g., compressionspring, Belleville spring, etc.), electrically (e.g., with the aid of aservo, which may be computer-controlled), pneumatically, etc. In somecases, actuator 560 (or another actuator) may be used to cause themiconeedles to be withdrawn from the skin, and/or the microneedles maybe withdrawn automatically after delivering and/or receiving fluid fromthe subject, e.g., without any intervention by the subject, or byanother person. Non-limiting examples of such techniques are discussedin detail below.

Another example is illustrated with reference to FIG. 8. In this figure,device 500 includes a deployment actuator 501, an adhesive 502 foradhesion of the device to the skin, and a substance transfer componentsystem 503. In FIG. 8, substance transfer component system 503 includesa plurality of microneedles 505 within recess 508, although othersubstance transfer components as discussed herein may also be used.Actuator 560 is shown at the top of device 500. Actuator 560 may be, forexample, a button, switch, slider, dial, etc. and may cause microneedles505 to move towards the skin when the device is placed on the skin. Forexample, the microneedles may be moved mechanically (e.g., compressionspring, Belleville spring, etc.), electrically (e.g., with the aid of aservo, which may be computer-controlled), pneumatically, etc., e.g., viacomponent 584 (e.g., a piston, a screw, a mechanical linkage, etc.). Insome cases, actuator 560 may also be able to withdraw the microneedlesfrom the skin after use, e.g., after a fluid is delivered and/orreceived from the skin.

Chamber 513, in this figure, is a self-contained vacuum chamber. Vacuumchamber 513 is in fluidic communication with recess 508 via channel 511,for example, as controlled by a controller or an actuator. Alsoillustrated in FIG. 8 is fluid reservoir 540, which may contain a fluidsuch as an anticoagulant. The fluid may be introduced into blood orother fluid received from the skin. Controlling fluid flow from fluidreservoir may be one or more suitable fluidic control elements, e.g.,pumps, nozzles, valves, or the like, for example, pump 541 in FIG. 8.

In certain embodiments, the substance transfer component may be fastenedon a deployment actuator. In some cases, the deployment actuator canbring the substance transfer component to the skin, and in certaininstances, insert the substance transfer component into the skin. Forexample, the substance transfer component can be moved mechanically,electrically (e.g., with the aid of a servo, which may becomputer-controlled), pneumatically, via a piston, a screw, a mechanicallinkage, or the like. In one set of embodiments, the deployment actuatorcan insert the substance transfer component into the skin at a speed ofat least about 0.1 cm/s, at least about 0.3 cm/s, about 1 cm/s, at leastabout 3 cm/s, at least about 10 cm/s, at least about 30 cm/s, at leastabout 1 m/s, at least about 2 m/s, at least about 3 m/s, at least about4 m/s, at least about 5 m/s, at least about 6 m/s, at least about 7 m/s,at least about 8 m/s, at least about 9 m/s, at least about 10 m/s, atleast about 12 m/s, etc., at the point where the substance transfercomponent initially contacts the skin. Without wishing to be bound byany theory, it is believed that relatively faster insertion speeds mayincrease the ability of the substance transfer component to penetratethe skin (without deforming the skin or causing the skin to move inresponse), and/or decrease the amount of pain felt by the application ofthe substance transfer component to the skin. Any suitable method ofcontrolling the penetration speed into the skin may be used, includethose described herein.

As mentioned, in some embodiments, blood or other bodily fluids may bestored within the device for later use and/or analysis. For example, thedevice may be attached to a suitable external apparatus able to analyzea portion of the device (e.g., containing the fluid), and/or theexternal apparatus may remove at least some of the blood or other fluidfrom the device for subsequent analysis and/or storage. In some cases,however, at least some analysis may be performed by the device itself,e.g., using one or more sensors, etc., contained within the device.

For example, as discussed in detail below, in some cases, a storagechamber may contain a reagent or a reaction entity able to react with ananalyte suspected of being present in the blood (or other fluid)entering the device, and in some cases, the reaction entity may bedetermined to determine the analyte. In some cases, the determinationmay be made externally of the device, e.g., by determining a colorchange or a change in fluorescence, etc. The determination may be madeby a person, or by an external apparatus able to analyze at least aportion of the device. In some cases, the determination may be madewithout removing blood from the device, e.g., from the storage chamber.(In other cases, however, blood or other fluid may first be removed fromthe device before being analyzed.) For example, the device may includeone or more sensors (e.g., ion sensors such as K⁺ sensors, colorimetricsensors, fluorescence sensors, etc.), and/or contain “windows” thatallow light to penetrate the device. The windows may be formed of glass,plastic, etc., and may be selected to be at least partially transparentto one or a range of suitable wavelengths, depending on the analyte orcondition to be determined. As a specific example, the entire device (ora portion thereof) may be mounted in an external apparatus, and lightfrom the external apparatus may pass through or otherwise interact withat least a portion of the device (e.g., be reflected or refracted viathe device) to determine the analyte and/or the reaction entity.

In one aspect, the device may be interfaced with an external apparatusable to determine an analyte contained within a fluid in the device, forexample within a storage chamber as discussed herein. For example, thedevice may be mounted on an external holder, the device may include aport for transporting fluid out of the device, the device may include awindow for interrogating a fluid contained within the device, or thelike. Examples may be seen in a U.S. provisional patent applicationfiled on even date herewith, entitled “Sampling Device Interfaces,”incorporated herein by reference in its entirety.

Thus, the device, in certain embodiments, may contain a portion able todetermine a fluid removed from the skin. For example, a portion of thedevice may contain a sensor, or reagents able to interact with ananalyte contained or suspected to be present within the received fluidfrom the subject, for example, a marker for a disease state. The sensormay be embedded within or integrally connected to the device, orpositioned remotely but with physical, electrical, and/or opticalconnection with the device so as to be able to sense a chamber within orfluid from the device. For example, the sensor may be in fluidiccommunication with fluid received from a subject, directly, via amicrofluidic channel, an analytical chamber, etc. The sensor may be ableto sense an analyte, e.g., one that is suspected of being in a fluidreceived from a subject. For example, a sensor may be free of anyphysical connection with the device, but may be positioned so as todetect the results of interaction of electromagnetic radiation, such asinfrared, ultraviolet, or visible light, which has been directed towarda portion of the device, e.g., a chamber within the device. As anotherexample, a sensor may be positioned on or within the device, and maysense activity in a chamber by being connected optically to the chamber.Sensing communication can also be provided where the chamber is incommunication with a sensor fluidly, optically or visually, thermally,pneumatically, electronically, or the like, so as to be able to sense acondition of the chamber. As one example, the sensor may be positioneddownstream of a chamber, within a channel such a microfluidic channel,on an external apparatus, or the like.

Thus, the invention provides, in certain embodiments, sensors able todetermine an analyte. Such determination may occur within the skin,and/or externally of the subject, e.g., within a device on the surfaceof the skin, depending on the embodiment. “Determine,” in this context,generally refers to the analysis of a species, for example,quantitatively or qualitatively, and/or the detection of the presence orabsence of the species. “Determining” may also refer to the analysis ofan interaction between two or more species, for example, quantitativelyor qualitatively, and/or by detecting the presence or absence of theinteraction, e.g. determination of the binding between two species. Thespecies may be, for example, a bodily fluid and/or an analyte suspectedof being present in the bodily fluid. “Determining” also means detectingor quantifying interaction between species.

Non-limiting examples of sensors include dye-based detection systems,affinity-based detection systems, microfabricated gravimetric analyzers,CCD cameras, optical detectors, optical microscopy systems, electricalsystems, thermocouples and thermistors, pressure sensors, etc. Those ofordinary skill in the art will be able to identify other suitablesensors. The sensor can include a colorimetric detection system in somecases, which may be external to the device, or microfabricated into thedevice in certain cases. As an example of a colorimetric detectionsystem, if a dye or a fluorescent entity is used (e.g. in a particle),the colorimetric detection system may be able to detect a change orshift in the frequency and/or intensity of the dye or fluorescententity.

Examples of sensors include, but are not limited to, pH sensors, opticalsensors, ion sensors, colorimetric sensors, a sensor able to detect theconcentration of a substance, or the like, e.g., as discussed herein.For instance, in one set of embodiments, the device may include an ionselective electrode. The ion selective electrode may be able todetermine a specific ion and/or ions such as K⁺, H⁺, Na⁺, Ag⁺, Pb²⁺,Cd²⁺, or the like. Various ion selective electrodes can be obtainedcommercially. As a non-limiting example, a potassium-selective electrodemay include an ion exchange resin membrane, using valinomycin, apotassium channel, as the ion carrier in the membrane to providepotassium specificity.

Examples of analytes that the sensor may be used to determine include,but are not limited to, pH or metal ions, proteins, nucleic acids (e.g.DNA, RNA, etc.), drugs, sugars (e.g., glucose), hormones (e.g.,estradiol, estrone, progesterone, progestin, testosterone,androstenedione, etc.), carbohydrates, or other analytes of interest.Other conditions that can be determined can include pH changes, whichmay indicate disease, yeast infection, periodontal disease at a mucosalsurface, oxygen or carbon monoxide levels which indicate lungdysfunction, and drug levels, e.g., legal prescription levels of drugssuch as coumadin, other drugs such as nicotine, or illegal such ascocaine. Further examples of analytes include those indicative ofdisease, such as cancer specific markers such as CEA and PSA, viral andbacterial antigens, and autoimmune indicators such as antibodies todouble stranded DNA, indicative of Lupus. Still other conditions includeexposure to elevated carbon monoxide, which could be from an externalsource or due to sleep apnea, too much heat (important in the case ofbabies whose internal temperature controls are not fullyself-regulating) or from fever. Still other potentially suitableanalytes include various pathogens such as bacteria or viruses, and/ormarkers produced by such pathogens.

As additional non-limiting examples, the sensor may contain an antibodyable to interact with a marker for a disease state, an enzyme such asglucose oxidase or glucose 1-dehydrogenase able to detect glucose, orthe like. The analyte may be determined quantitatively or qualitatively,and/or the presence or absence of the analyte within the received fluidmay be determined in some cases. Those of ordinary skill in the art willbe aware of many suitable commercially-available sensors, and thespecific sensor used may depend on the particular analyte being sensed.For instance, various non-limiting examples of sensor techniques includepressure or temperature measurements, spectroscopy such as infrared,absorption, fluorescence, UV/visible, FTIR (“Fourier Transform InfraredSpectroscopy”), or Raman; piezoelectric measurements; immunoassays;electrical measurements, electrochemical measurements (e.g.,ion-specific electrodes); magnetic measurements, optical measurementssuch as optical density measurements; circular dichroism; lightscattering measurements such as quasielectric light scattering;polarimetry; refractometry; chemical indicators such as dyes; orturbidity measurements, including nephelometry.

In one set of embodiments, a sensor in the device may be used todetermine a condition of the blood present within the device. Forexample, the sensor may indicate the condition of analytes commonlyfound within the blood, for example, O₂, K⁺, hemoglobin, Na⁺, glucose,or the like. As a specific non-limiting example, in some embodiments,the sensor may determine the degree of hemolysis within blood containedwithin the device. Without wishing to be bound by any theory, it isbelieved that in some cases, hemolysis of red blood cells may cause therelease of potassium ions and/or free hemoglobin into the blood. Bydetermining the levels of potassium ions, and/or hemoglobin (e.g., bysubjecting the device and/or the blood to separate cells from plasma,then determining hemoglobin in the plasma using a suitable colorimetricassay), the amount of blood lysis or “stress” experienced by the bloodcontained within the device may be determined. Accordingly, in one setof embodiments, the device may indicate the usability of the blood (orother fluid) contained within the device, e.g., by indicating the degreeof stress or the amount of blood lysis. Other examples of devicessuitable for indicating the usability of the blood (or other fluid)contained within the device are also discussed herein (e.g., byindicating the amount of time blood has been contained in the device,the temperature history of the device, etc.).

For instance, fluids received from the subject will often containvarious analytes within the body that are important for diagnosticpurposes, for example, markers for various disease states, such asglucose (e.g., for diabetics); other example analytes include ions suchas sodium, potassium, chloride, calcium, magnesium, and/or bicarbonate(e.g., to determine dehydration); gases such as carbon dioxide oroxygen; H⁺ (i.e., pH); metabolites such as urea, blood urea nitrogen orcreatinine; hormones such as estradiol, estrone, progesterone,progestin, testosterone, androstenedione, etc. (e.g., to determinepregnancy, illicit drug use, or the like); or cholesterol. Otherexamples include insulin, or hormone levels. As discussed herein,certain embodiments of the present invention are generally directed atmethods for receiving fluids from the body, and optionally determiningone or more analytes within the received fluid. Thus, in someembodiments, at least a portion of the fluid may be stored, and/oranalyzed to determine one or more analytes, e.g., a marker for a diseasestate, or the like. The fluid received from the skin may be subjected tosuch uses, and/or one or more materials previously delivered to the skinmay be subject to such uses.

Still other potentially suitable analytes include various pathogens suchas bacteria or viruses, and/or markers produced by such pathogens. Thus,in certain embodiments of the invention, as discussed below, one or moreanalytes within the pooled region of fluid may be determined in somefashion, which may be useful in determining a past, present and/orfuture condition of the subject.

In some embodiments, the device may connected to an external apparatusfor determining at least a portion of the device, a fluid removed fromthe device, an analyte suspected of being present within the fluid, orthe like. For example, the device may be connected to an externalanalytical apparatus, and fluid removed from the device for lateranalysis, or the fluid may be analyzed within the device in situ, e.g.,by adding one or more reaction entities to the device, for instance, toa storage chamber, or to analytical chamber within the device. Forexample, in one embodiment, the external apparatus may have a port orother suitable surface for mating with a port or other suitable surfaceon the device, and blood or other fluid can be removed from the deviceusing any suitable technique, e.g., using vacuum or pressure, etc. Theblood may be removed by the external apparatus, and optionally, storedand/or analyzed in some fashion. For example, in one set of embodiments,the device may include an exit port for removing a fluid from the device(e.g., blood). In some embodiments, fluid contained within a storagechamber in the device may be removed from the device, and stored forlater use or analyzed outside of the device. In some cases, the exitport may be separate from the substance transfer component. An exampleis shown with exit port 670 and substance transfer component 620 indevice 600 in FIG. 7. As shown in this figure, the exit port can be influidic communication with vacuum chamber 610, which can also serve as afluid reservoir in some cases. Other methods for removing blood or otherfluids from the device include, but are not limited to, removal using avacuum line, a pipette, extraction through a septum instead of an exitport, or the like. In some cases, the device may also be positioned in acentrifuge and subjected to various g forces (e.g., to a centripetalforce of at least 50 g), e.g., to cause at separation of cells or othersubstances within a fluid within the device to occur.

In one set of embodiments, the device may include an anticoagulant or astabilizing agent for stabilizing the fluid received from the skin. Theanticoagulant may be located in a vacuum chamber and/or a collectionchamber, depending on the application. For example, the fluid may bestored within the device for a certain period of time, and/or the device(or a portion thereof) may be moved or shipped to another location foranalysis or later use. For instance, a device may contain anticoagulantor a stabilizing agent in a storage chamber. In some cases, more thanone anticoagulant may be used, e.g., in the same storage chamber, or inmore than one storage chamber.

As a specific non-limiting example, an anticoagulant may be used forblood received from the skin. Examples of anticoagulants include, butare not limited to, heparin, citrate, thrombin, oxalate,ethylenediaminetetraacetic acid (EDTA), sodium polyanethol sulfonate,acid citrate dextrose. Other agents may be used in conjunction orinstead of anticoagulants, for example, stabilizing agents such assolvents, diluents, buffers, chelating agents, antioxidants, bindingagents, preservatives, antimicrobials, or the like. Examples ofpreservatives include, for example, benzalkonium chloride,chlorobutanol, parabens, or thimerosal. Non-limiting examples ofantioxidants include ascorbic acid, glutathione, lipoic acid, uric acid,carotenes, alpha-tocopherol, ubiquinol, or enzymes such as catalase,superoxide dismutase, or peroxidases. Examples of microbials include,but are not limited to, ethanol or isopropyl alcohol, azides, or thelike. Examples of chelating agents include, but are not limited to,ethylene glycol tetraacetic acid or ethylenediaminetetraacetic acid.Examples of buffers include phosphate buffers such as those known toordinary skill in the art.

In one set of embodiments, at least a portion of the device may becolored to indicate the anticoagulant(s) contained within the device. Insome cases, the colors used may be identical or equivalent to thatcommercially used for Vacutainers™, Vacuettes™, or othercommercially-available phlebotomy equipment. For example, lavenderand/or purple may indicate ethylenediaminetetraacetic acid, light bluemay indicate citrate, dark blue may indicate ethylenediaminetetraaceticacid, green may indicate heparin, gray may indicate a fluoride and/or anoxalate, orange may indicate a thrombin, yellow may indicate sodiumpolyanethol sulfonate and/or acid citrate dextrose, black may indicatecitrate, brown may indicate heparin, etc. In other embodiments, however,other coloring systems may be used.

Other coloring systems may be used in other embodiments of theinvention, not necessarily indicative of anti-coagulants. For example,in one set of embodiments, the device carries a color indicative of arecommended bodily use site for the device, e.g., a first colorindicative of a device suitable for placement on the back, a secondcolor indicative of a device suitable for placement on a leg, a thirdcolor indicative of a device suitable for placement on the arm, etc.

As mentioned, in one set of embodiments, a device of the invention asdiscussed herein may be shipped to another location for analysis. Insome cases, the device may include an anticoagulant or a stabilizingagent contained within the device, e.g., within a storage chamber forthe fluid. Thus, for example, fluid such as blood received from the skinmay be delivered to a chamber (e.g., a storage chamber) within thedevice, then the device, or a portion of the device (e.g., a module) maybe shipped to another location for analysis. Any form of shipping may beused, e.g., via mail.

Non-limiting examples of various devices of the invention are shown inFIG. 1. In FIG. 1A, device 90 is used for receiving a fluid from asubject when the device is placed on the skin of a subject. Device 90includes sensor 95 and substance transfer component 92, e.g., a needle,a microneedle, etc., as discussed herein. In fluidic communication withsubstance transfer component 92 via fluidic channel 99 is sensingchamber 97. In one embodiment, sensing chamber 97 may contain agentssuch as particles, enzymes, dyes, etc., for analyzing bodily fluids,such as interstitial fluid or blood. In some cases, fluid may bereceived using substance transfer component 92 by a vacuum, for example,a self-contained vacuum contained within device 90. Optionally, device90 also contains a display 94 and associated electronics 93, batteriesor other power supplies, etc., which may be used to display sensorreadings obtained via sensor 95. In addition, device 90 may alsooptionally contain memory 98, transmitters for transmitting a signalindicative of sensor 95 to a receiver, etc.

In the example shown in FIG. 1A, device 90 may contain a vacuum source(not shown) that is self-contained within device 90, although in otherembodiments, the vacuum source may be external to device 90. (In stillother instances, other systems may be used to deliver and/or receivefluid from the skin, as is discussed herein.) In one embodiment, afterbeing placed on the skin of a subject, the skin may be drawn upward intoa recess containing substance transfer component 92, for example, uponexposure to the vacuum source. Access to the vacuum source may becontrolled by any suitable method, e.g., by piercing a seal or a septum;by opening a valve or moving a gate, etc. For instance, upon activationof device 90, e.g., by the subject, remotely, automatically, etc., thevacuum source may be put into fluidic communication with the recess suchthat skin is drawn into the recess containing substance transfercomponent 92 due to the vacuum. Skin drawn into the recess may come intocontact with substance transfer component 92 (e.g., solid or hollowneedles), which may, in some cases, pierce the skin and allow a fluid tobe delivered and/or received from the skin. In another embodiment,substance transfer component 92 may be actuated and moved downward tocome into contact with the skin, and optionally retracted after use.

Another non-limiting example of a device is shown in FIG. 1B. Thisfigure illustrates a device useful for delivering a fluid to thesubject. Device 90 in this figure includes substance transfer component92, e.g., a needle, a microneedle, etc., as discussed herein. In fluidiccommunication with substance transfer component 92 via fluidic channel99 is chamber 97, which may contain a drug or other agent to bedelivered to the subject. In some cases, fluid may be delivered with apressure controller, and/or received using substance transfer component92 by a vacuum, for example, a self-contained vacuum contained withindevice 90. For instance, upon creating a vacuum, skin may be drawn uptowards substance transfer component 92, and substance transfercomponent 92 may pierce the skin. Fluid from chamber 97 can then bedelivered into the skin through fluid channel 99 and substance transfercomponent 92. Optionally, device 90 also contains a display 94 andassociated electronics 93, batteries or other power supplies, etc.,which may be used control delivery of fluid to the skin. In addition,device 90 may also optionally contain memory 98, transmitters fortransmitting a signal indicative of device 90 or fluid delivery to areceiver, etc.

Yet another non-limiting example of a device of the invention is shownin FIG. 2. FIG. 2A illustrates a view of the device (with the coverremoved), while FIG. 2B schematically illustrates the device incross-section. In FIG. 2B, device 50 includes a needle 52 containedwithin a recess 55. Needle 52 may be solid or hollow, depending on theembodiment. Device 50 also includes a self-contained vacuum chamber 60,which wraps around the central portion of the device where needle 52 andrecess 55 are located. A channel 62 connects vacuum chamber 60 withrecess 55, separated by a foil or a membrane 67. Also shown in device 50is button 58. When pushed, button 58 breaks foil 67, thereby connectingvacuum chamber 50 with recess 55, creating a vacuum in recess 55. Thevacuum may be used, for example, to draw skin into recess 55, preferablysuch that it contacts needle 52 and pierces the surface, thereby gainingaccess to an internal fluid. The fluid may be controlled, for example,by controlling the size of needle 52, and thereby the depth ofpenetration. For example, the penetration may be limited to theepidermis, e.g., to collect interstitial fluid, or to the dermis, e.g.,to collect blood. In some cases, the vacuum may also be used to at leastpartially secure device 50 on the surface of the skin, and/or to assistin the receiving of fluid from the skin. For instance, fluid may flowinto channel 62 under action of the vacuum, and optionally to sensor 61,e.g., for detection of an analyte contained within the fluid. Forinstance, sensor 61 may produce a color change if an analyte is present,or otherwise produce a detectable signal.

Other components may be added to the example of the device illustratedin FIG. 2, in some embodiments of the invention. For example, device 50may contain a cover, displays, ports, transmitters, sensors, channelssuch as microfluidic channels, chambers, and/or various electronics,e.g., to control or monitor fluid transport into or out of device 50, todetermine an analyte present within a fluid delivered and/or receivedfrom the skin, to determine the status of the device, to report ortransmit information regarding the device and/or analytes, or the like,as is discussed in more detail herein. As another example, device 50 maycontain an adhesive, e.g., on surface 54, for adhesion of the device tothe skin.

Yet another non-limiting example is illustrated with reference to FIG.2C. In this example, device 500 includes a deployment actuator 501, andan associated substance transfer component system 503. Substancetransfer component system 503 includes a plurality of needles ormicroneedles 505, although other substance transfer components asdiscussed herein may also be used. Also shown in FIG. 5 is sensor 510,connected via channels 511 to recess 508 containing needles ormicroneedles 505. Chamber 513 may be a self-contained vacuum chamber,and chamber 513 may be in fluidic communication with recess 508 viachannel 511, for example, as controlled by a controller or an actuator(not shown). In this figure, device 500 also contains display 525, whichis connected to sensor 510 via electrical connection 522. As an exampleof use of device 500, when fluid is drawn from the skin (e.g., blood,interstitial fluid, etc.), the fluid may flow through channel 511 to bedetermined by sensor 510, e.g., due to action of the vacuum from vacuumchamber 513. In some cases, the vacuum is used, for example, to drawskin into recess 508, preferably such that it contacts needles ormicroneedles 505 and pierces the surface of the skin to gain access to afluid internal of the subject, such as blood or interstitial fluid, etc.The fluid may be controlled, for example, by controlling the size ofneedle 505, and thereby the depth of penetration. For example, thepenetration may be limited to the epidermis, e.g., to collectinterstitial fluid, or to the dermis, e.g., to collect blood. Upondetermination of the fluid and/or an analyte present or suspected to bepresent within the fluid, a microprocessor or other controller maydisplay on display 525 a suitable signal. As is discussed below, adisplay is shown in this figure by way of example only; in otherembodiments, no display may be present, or other signals may be used,for example, lights, smell, sound, feel, taste, or the like.

In some cases, more than one substance transfer component system may bepresent within the device. For instance, the device may be able to beused repeatedly, and/or the device may be able to deliver and/or receivefluid at more than one location on a subject, e.g., sequentially and/orsimultaneously. In some cases, the device may be able to simultaneouslydeliver and receive fluid to and from a subject. A non-limiting exampleof a device having more than one substance transfer component system isillustrated with reference to FIG. 2E. In this example, device 500contains a plurality of structures such as those described herein fordelivering and/or receiving fluid from a subject. For example, device500 in this example contains 3 such units, although any number of unitsare possible in other embodiments. In this example, device 500 containsthree such substance transfer component systems 575. Each of thesesubstance transfer component systems may independently have the same ordifferent structures, depending on the particular application, and theymay have structures such as those described herein.

In some embodiments, the device may be an electrical and/or a mechanicaldevice applicable or affixable to the surface of the skin, e.g., usingadhesive, or other techniques such as those described herein. Theadhesive may be permanent or temporary, and may be used to affix thedevice to the surface of the skin. The adhesive may be any suitableadhesive, for example, a pressure sensitive adhesive, a contactadhesive, a permanent adhesive, a hydrogel, a cyanoacrylate, a glue, agum, hot melts, an epoxy, or the like. In some cases, the adhesive ischosen to be biocompatible or hypoallergenic.

In another set of embodiments, the device may be mechanically held tothe skin, for example, the device may include mechanical elements suchas straps, belts, buckles, strings, ties, elastic bands, or the like.For example, a strap may be worn around the device to hold the device inplace against the skin of the subject. In yet another set ofembodiments, a combination of these and/or other techniques may be used.As one non-limiting example, the device may be affixed to a subject'sarm or leg using adhesive and a strap.

As another example, the device may be a handheld device that is appliedto the surface of the skin of a subject. In some cases, however, thedevice may be sufficiently small or portable that the subject canself-administer the device. In certain embodiments, the device may alsobe powered. In some instances, the device may be applied to the surfaceof the skin, and is not inserted into the skin. In other embodiments,however, at least a portion of the device may be inserted into the skin,for example, mechanically. For example, in one embodiment, the devicemay include a cutter, such as a hypodermic needle, a knife blade, apiercing element (e.g., a solid or hollow needle), or the like, asdiscussed herein.

Any or all of the arrangements described herein can be providedproximate a subject, for example on or proximate a subject's skin.Activation of the devices can be carried out in a variety of ways. Inone embodiment, a device can be applied to a subject and a region of thedevice activated (e.g., pushed, pressed, or tapped by a user) to injecta needle or a microneedle so as to access interstitial fluid. The sameor a different tapping or pushing action can activate a vacuum source,open and/or close one or more of a variety of valves, or the like. Thedevice can be a simple one in which it is applied to the skin andoperates automatically (where e.g., application to the skin accessesinterstitial fluid and draws interstitial fluid into an analysis region)or the device can be applied to the skin and one tapping or otheractivation can cause fluid to flow through administration of a needle ora microneedle, opening of a valve, activation of vacuum, or anycombination. Any number of activation protocols can be carried out by auser repeatedly pushing or tapping a location or selectively,sequentially, and/or periodically activating a variety of switches. Inanother arrangement, activation of needles or microneedles, creation ofsuction blisters, opening and/or closing of valves, and other techniquesto facilitate one or more analysis can be carried out electronically orin other manners facilitated by the subject or by an outside controllingentity. For example, a device or patch can be provided proximate asubject's skin and a radio frequency, electromagnetic, or other signalcan be provided by a nearby controller or a distant source to activateany of the needles, blister devices, valves or other components of thedevices described so that any assay or assays can be carried out asdesired.

In some embodiments, fluid may be delivered to the subject, and suchfluids may contain materials useful for delivery, e.g., forming at leasta portion of the fluid, dissolved within the fluid, carried by the fluid(e.g., suspended or dispersed), or the like. Examples of suitablematerials include, but are not limited to, particles such asmicroparticles or nanoparticles, a chemical, a drug or a therapeuticagent, a diagnostic agent, a carrier, or the like.

As used herein, the term “fluid” generally refers to a substance thattends to flow and to conform to the outline of its container. Typically,fluids are materials that are unable to withstand a static shear stress,and when a shear stress is applied, the fluid experiences a continuingand permanent distortion. The fluid may have any suitable viscosity thatpermits at least some flow of the fluid. Non-limiting examples of fluidsinclude liquids and gases, but may also include free-flowing solidparticles, viscoelastic fluids, and the like. For example, the fluid mayinclude a flowable matrix or a gel, e.g., formed from biodegradableand/or biocompatible material such as polylactic acid, polyglycolicacid, poly(lactic-co-glycolic acid), etc., or other similar materials.

In some cases, fluids or other materials delivered to the subject may beused for indication of a past, present and/or future condition of thesubject. Thus, the condition of the subject to be determined may be onethat is currently existing in the subject, and/or one that is notcurrently existing, but the subject is susceptible or otherwise is at anincreased risk to that condition. The condition may be a medicalcondition, e.g., diabetes or cancer, or other physiological conditions,such as dehydration, pregnancy, illicit drug use, or the like. In oneset of embodiments, the materials may include a diagnostic agent, forexample, one which can determine an analyte within the subject, e.g.,one that is a marker for a disease state. As a specific non-limitingexample, material delivered to the skin, e.g., to the dermis orepidermis, to a pooled region of fluid, etc., of a subject may include aparticle including an antibody directed at a marker produced bybacteria.

In other cases, however, the materials delivered to the subject may beused to determine conditions that are external to the subject. Forexample, the materials may contain reaction entities able to recognizepathogens or other environmental conditions surrounding the subject, forexample, an antibody able to recognize an external pathogen (or pathogenmarker). As a specific example, the pathogen may be anthrax and theantibody may be an antibody to anthrax spores. As another example, thepathogen may be a Plasmodia (some species of which causes malaria) andthe antibody may be an antibody that recognizes the Plasmodia.

According to one aspect of the invention, the device is of a relativelysmall size. In some embodiments, the device may be sized such that it iswearable and/or carryable by a subject. For example, the device may beself-contained, needing no wires, cables, tubes, external structuralelements, or other external support. The device may be positioned on anysuitable position of the subject, for example, on the arm or leg, on theback, on the abdomen, etc. As mentioned, in some embodiments, the devicemay be affixed or held onto the surface of the skin using any suitabletechnique, e.g., using adhesives, mechanical elements such as straps,belts, buckles, strings, ties, elastic bands, or the like. In somecases, the device may be positioned on the subject such that the subjectis able to move around (e.g., walking, exercising, typing, writing,drinking or eating, using the bathroom, etc.) while wearing the device.For example, the device may have a mass and/or dimensions such that thesubject is able to wear the device for at least about 5 minutes, and insome cases for longer periods of time, e.g., at least about 10 minutes,at least about 15 minutes, at least about 30 minutes, at least about 45minutes, at least about 1 hour, at least about 3 hours, at least 5hours, at least about 8 hours, at least about 1 day, at least about 2days, at least about 4 days, at least about 1 week, at least about 2weeks, at least about 4 weeks, etc.

In some embodiments, the device is relatively lightweight. For example,the device may have a mass of no more than about 1 kg, no more thanabout 300 g, no more than about 150 g, no more than about 100 g, no morethan about 50 g, no more than about 30 g, no more than about 25 g, nomore than about 20 g, no more than about 10 g, no more than about 5 g,or no more than about 2 g. For instance, in various embodiments, thedevice has a mass of between about 2 g and about 25 g, a mass of betweenabout 2 g and about 10 g, a mass of between 10 g and about 50 g, a massof between about 30 g and about 150 g, etc.

The device, in some cases, may be relatively small. For example, thedevice may be constructed and arranged to lie relatively close to theskin. Thus, for instance, the device may have a largest verticaldimension, extending from the skin of the subject when the device ispositioned on the skin, of no more than about 25 cm, no more than about10 cm, no more than about 7 cm, no more than about 5 cm, no more thanabout 3 cm, no more than about 2 cm, no more than about 1 cm, no morethan about 8 mm, no more than about 5 mm, no more than about 3 mm, nomore than about 2 mm, no more than about 1 mm, or no more than about 0.5mm. In some cases, the device may have a largest vertical dimension ofbetween about 0.5 cm and about 1 cm, between about 2 and about 3 cm,between about 2.5 cm and about 5 cm, between about 2 cm and about 7 cm,between about 0.5 mm and about 7 cm, etc.

In another set of embodiments, the device may have a relatively smallsize. For example, the device may have a largest lateral dimension(e.g., parallel to the skin) of no more than about 25 cm, no more thanabout 10 cm, no more than about 7 cm, no more than about 5 cm, no morethan about 3 cm, no more than about 2 cm, or no more than about 1 cm. Insome cases, the device may have a largest lateral dimension of betweenabout 0.5 cm and about 1 cm, between about 2 and about 3 cm, betweenabout 2.5 cm and about 5 cm, between about 2 cm and about 7 cm, etc.

Combinations of these and/or other dimensions are also possible in otherembodiments. As non-limiting examples, the device may have a largestlateral dimension of no more than about 5 cm, a largest verticaldimension of no more than about 1 cm, and a mass of no more than about25 g; or the device may have a largest lateral dimension of no more thanabout 5 cm, a largest vertical dimension of no more than about 1 cm, anda mass of no more than about 25 g; etc.

In certain embodiments, the device may also contain an activator. Theactivator may be constructed and arranged to cause exposure of thesubstance transfer component to the skin upon activation of theactivator. For example, the activator may cause a chemical to bereleased to contact the skin, a microneedle to be driven into the skin,a vacuum to be applied to the skin, a jet of fluid to be directed to theskin, or the like. The activator may be activated by the subject, and/orby another person (e.g., a health care provider), or the device itselfmay be self-activating, e.g., upon application to the skin of a subject.The activator may be activated once, or multiple times in some cases.

The device may be activated, for example, by pushing a button, pressinga switch, moving a slider, turning a dial, or the like. The subject,and/or another person, may activate the activator. In some cases, thedevice may be remotely activated. For example, a health care providermay send an electromagnetic signal which is received by the device inorder to activate the device, e.g., a wireless signal, a radio signal,etc.

In one set of embodiments, the device may include channels such asmicrofluidic channels, which may be used to deliver and/or receivefluids and/or other materials into or out of the skin, e.g., within thepooled region of fluid. In some cases, the microfluidic channels are influid communication with a substance transfer component that is used todeliver and/or receive fluids to or from the skin. For example, in oneset of embodiments, the device may include a hypodermic needle that canbe inserted into the skin, and fluid may be delivered into the skin viathe needle and/or received from the skin via the needle. The device mayalso include one or more microfluidic channels to contain fluid fordelivery to the needle, e.g., from a source of fluid, and/or to receivefluid from the skin, e.g., for delivery to an analytical chamber withinthe device, to a reservoir for later analysis, or the like.

In some cases, more than one chamber may be present within the device,and in some cases, some or all of the chambers may be in fluidiccommunication, e.g., via channels such as microfluidic channels. Invarious embodiments, a variety of chambers and/or channels may bepresent within the device, depending on the application. For example,the device may contain chambers for sensing an analyte, chambers forholding reagents, chambers for controlling temperature, chambers forcontrolling pH or other conditions, chambers for creating or bufferingpressure or vacuum, chambers for controlling or dampening fluid flow,mixing chambers, or the like.

Thus, in one set of embodiments, the device may include a microfluidicchannel. As used herein, “microfluidic,” “microscopic,” “microscale,”the “micro-” prefix (for example, as in “microchannel”), and the likegenerally refers to elements or articles having widths or diameters ofless than about 1 mm, and less than about 100 microns (micrometers) insome cases. In some embodiments, larger channels may be used instead of,or in conjunction with, microfluidic channels for any of the embodimentsdiscussed herein. For examples, channels having widths or diameters ofless than about 10 mm, less than about 9 mm, less than about 8 mm, lessthan about 7 mm, less than about 6 mm, less than about 5 mm, less thanabout 4 mm, less than about 3 mm, or less than about 2 mm may be used incertain instances. In some cases, the element or article includes achannel through which a fluid can flow. In all embodiments, specifiedwidths can be a smallest width (i.e. a width as specified where, at thatlocation, the article can have a larger width in a different dimension),or a largest width (i.e. where, at that location, the article has awidth that is no wider than as specified, but can have a length that isgreater). Thus, for instance, the microfluidic channel may have anaverage cross-sectional dimension (e.g., perpendicular to the directionof flow of fluid in the microfluidic channel) of less than about 1 mm,less than about 500 microns, less than about 300 microns, or less thanabout 100 microns. In some cases, the microfluidic channel may have anaverage diameter of less than about 60 microns, less than about 50microns, less than about 40 microns, less than about 30 microns, lessthan about 25 microns, less than about 10 microns, less than about 5microns, less than about 3 microns, or less than about 1 micron.

A “channel,” as used herein, means a feature on or in an article (e.g.,a substrate) that at least partially directs the flow of a fluid. Insome cases, the channel may be formed, at least in part, by a singlecomponent, e.g. an etched substrate or molded unit. The channel can haveany cross-sectional shape, for example, circular, oval, triangular,irregular, square or rectangular (having any aspect ratio), or the like,and can be covered or uncovered (i.e., open to the external environmentsurrounding the channel). In embodiments where the channel is completelycovered, at least one portion of the channel can have a cross-sectionthat is completely enclosed, and/or the entire channel may be completelyenclosed along its entire length with the exception of its inlet andoutlet.

A channel may have any aspect ratio, e.g., an aspect ratio (length toaverage cross-sectional dimension) of at least about 2:1, more typicallyat least about 3:1, at least about 5:1, at least about 10:1, etc. Asused herein, a “cross-sectional dimension,” in reference to a fluidic ormicrofluidic channel, is measured in a direction generally perpendicularto fluid flow within the channel. A channel generally will includecharacteristics that facilitate control over fluid transport, e.g.,structural characteristics and/or physical or chemical characteristics(hydrophobicity vs. hydrophilicity) and/or other characteristics thatcan exert a force (e.g., a containing force) on a fluid. The fluidwithin the channel may partially or completely fill the channel. In somecases the fluid may be held or confined within the channel or a portionof the channel in some fashion, for example, using surface tension(e.g., such that the fluid is held within the channel within a meniscus,such as a concave or convex meniscus). In an article or substrate, some(or all) of the channels may be of a particular size or less, forexample, having a largest dimension perpendicular to fluid flow of lessthan about 5 mm, less than about 2 mm, less than about 1 mm, less thanabout 500 microns, less than about 200 microns, less than about 100microns, less than about 60 microns, less than about 50 microns, lessthan about 40 microns, less than about 30 microns, less than about 25microns, less than about 10 microns, less than about 3 microns, lessthan about 1 micron, less than about 300 nm, less than about 100 nm,less than about 30 nm, or less than about 10 nm or less in some cases.In one embodiment, the channel is a capillary.

In some cases, the device may contain one or more chambers or reservoirsfor holding fluid. In some cases, the chambers may be in fluidiccommunication with one or more substance transfer components and/or oneor more microfluidic channels. For instance, the device may contain achamber for collecting fluid received from a subject (e.g., for storageand/or later analysis), a chamber for containing a fluid for delivery tothe subject (e.g., blood, saline, optionally containing drugs, hormones,vitamins, pharmaceutical agents, or the like), etc.

After receiving the fluid into the device, the device, or a portionthereof, may be removed from the skin of the subject, e.g., by thesubject or by another person. For example, the entire device may beremoved, or a portion of the device containing the storage reservoir maybe removed from the device, and optionally replaced with another storagereservoir. Thus, for instance, in one embodiment, the device may containtwo or more modules, for example, a first module that is able to causereceiving of fluid from the skin into a storage reservoir, and a secondmodule containing the storage module. In some cases, the modulecontaining the storage reservoir may be removed from the device. Otherexamples of modules and modular systems are discussed below; otherexamples are discussed in U.S. Provisional Patent Application Ser. No.61/256,931, filed Oct. 30, 2009, entitled “Modular Systems forApplication to the Skin,” incorporated by reference herein in itsentirety.

As another example, the device may include at least two modules manuallyseparable from each other, including a first module comprising a vacuumchamber, and a second module comprising other components such as thosedescribed herein. In some embodiments, the modules may be separablewithout the use of tools. For example, the second module may include oneor more components such as a substance transfer component (e.g., aneedle or microneedle), an applicator region such as a recess, adeployment actuator such as a flexible concave member, a collectionchamber, a sensor, a processor, or the like. As a specific example, thefirst module may be defined entirely or partially by a vacuum chamber,and the first module may be removed and replaced with a fresh vacuumchamber, during or between uses. Thus, for instance, the first modulemay be inserted into the device when blood or other bodily fluids aredesired to be received from a subject, and optionally, used to causeblood to be received from the subject, e.g., as discussed above withreference to FIG. 13A.

In one set of embodiments, the first module may be substantiallycylindrical, and in some embodiments, the first module may be aVacutainer™ tube, a Vacuette™ tube, or other commercially-availablevacuum tube, or other vacuum source such as is described herein. In someembodiments, a Vacutainer™ or Vacuette™ tube that is used may have amaximum length of no more than about 75 mm or about 100 mm and adiameter of no more than about 16 mm or about 13 mm. The device, incertain embodiments, may also contain an adaptor able to hold orimmobilize such tubes on the device, for example, a clamp. Otherexamples of adaptors are discussed in detail herein. In some cases, thedevice may have a shape or geometry that mimics a Vacutainer™ orVacuette™ tube, e.g., one having the above dimensions. The device, insome embodiments, is substantially cylindrically symmetric.

The received fluid may then be sent to a clinical and/or laboratorysetting, e.g., for analysis. In some embodiments, the entire device maybe sent to the clinical and/or laboratory setting; in other embodiments,however, only a portion of the device (e.g., a module containing astorage reservoir containing the fluid) may be sent to the clinicaland/or laboratory setting. In some cases, the fluid may be shipped usingany suitable technique (e.g., by mail, by hand, etc.). In certaininstances, the subject may give the fluid to appropriate personnel at aclinical visit. For instance, a doctor may prescribe a device asdiscussed above for use by the subject, and at the next doctor visit,the subject may give the doctor the received fluid, e.g., containedwithin a device or module.

In some aspects, the device may contain an indicator. The indicator maybe used for determining a condition of a fluid contained within thedevice, e.g., within a fluid storage chamber or a fluid reservoir. Insome embodiments, the indicator may indicate one or more conditionsassociated with the introduction of fluid into the storage componentand/or one or more conditions associated with storage of fluid in thestorage component. For example, the indicator may indicate the conditionof blood or ISF within the device, e.g., as the device is beingtransported or shipped to a clinical or a laboratory setting. Theindicator may indicate the condition of the blood through any suitabletechnique, e.g., visually (such as with a color change), using adisplay, by producing a sound, etc. For instance, the indicator may havea display that is green if the fluid has not been exposed to certaintemperatures or if there is no adverse chemical reaction present withinthe fluid (e.g., a change in pH, growth of microorganisms, etc.), but isyellow or red if adverse conditions are or have been present (e.g.,exposure to temperatures that are too extreme, growth of microorganisms,etc.). In other embodiments, the display may display a visual message, asound may be produced by the device, or the like.

In some cases, the indicator may be activated upon the accessing offluid by the access component and/or introduction of fluid into thestorage component. In one set of embodiments, the indicator may beactivated upon the introduction of fluid within a fluid storagereservoir, upon activation of the device (e.g., to receive fluid from asubject, as discussed below), upon activation by a user (e.g., by thesubject, or another person), etc.

In some cases, the indicator may determine the condition of fluid withina fluid storage reservoir within the device using one or more suitablesensors, for example, pH sensors, temperature sensors (e.g.,thermocouples), oxygen sensors, or the like. For instance, a sensor maybe present within or proximate the fluid storage reservoir fordetermining the temperature of the fluid within the fluid storagereservoir. In some cases, for example, more than one sensor measurementmay be taken, e.g., at multiple points of time or even continuously. Insome cases, the indicator may also record the sensor determinations,e.g., for analysis or later study.

In certain embodiments, time information may be determined and/orrecorded by the indicator. For example, the time fluid enters a fluidstorage reservoir may be recorded, e.g., using a time/date stamp (e.g.,absolute time), and/or using the duration of time that fluid has beenpresent within the fluid storage reservoir. The time information mayalso be recorded in some embodiments.

As discussed, in one set of embodiments, information from sensors and/ortime information may be used to determine a condition of the fluidwithin the fluid storage reservoir. For example, if certain limits aremet or exceeded, the indicator may indicate that, as discussed above. Asa specific non-limiting example, if the temperature of the device is toolow (e.g., reaches 0° C.) or too high (e.g., reaches 100° C. or 37° C.),this may be displayed by a display on the indicator. Thus, fluid exposedto temperature extremes may be identified, e.g., as being problematic orspoiled. As a another non-limiting example, it may be desired to keepthe pH of fluid within the device within certain conditions, and if thepH is exceeded (e.g., too acidic or too basic), this may be displayed bya display on the indicator, for example, if the pH is less than 6 or 5,or greater than 8 or 9. In some cases, the time that fluid is presentwithin the device may be kept within certain limits as well, as anothercondition. For example, the indicator may indicate that fluid has beenpresent within the device for more than about 12 hours, more than about18 hours, or more than about 24 hours, which may indicate the fluid asbeing problematic, spoiled, etc.

In one set of embodiments, conditions such as these may also be combined(e.g., time and temperature). Thus, for example, fluid exposed to afirst temperature may be allowed to be present within the device for afirst time, while fluid exposed to a second temperature may be allowedto be present within the device for a second time, before the indicatordisplays this.

In some embodiments, the indicator may record and/or transmit sensor ortime information. This may be recorded and/or transmitted using anysuitable format. For instance, the information may be transmitted usinga wireless signal, a radio signal, etc., or recorded on any suitableelectronic media, e.g., on a microchip, flash drive, optically,magnetically, etc.

A variety of materials and methods, according to certain aspects of theinvention, can be used to form the device, e.g., microfluidic channels,chambers, etc. For example, various components of the invention can beformed from solid materials, in which the channels can be formed viamicromachining, film deposition processes such as spin coating andchemical vapor deposition, laser fabrication, photolithographictechniques, etching methods including wet chemical or plasma processes,and the like. See, for example, Scientific American, 248:44-55, 1983(Angell, et al).

In one set of embodiments, various components of the systems and devicesof the invention can be formed of a polymer, for example, an elastomericpolymer such as polydimethylsiloxane (“PDMS”), polytetrafluoroethylene(“PTFE” or Teflon®), or the like. For instance, according to oneembodiment, a microfluidic channel may be implemented by fabricating thefluidic system separately using PDMS or other soft lithographytechniques (details of soft lithography techniques suitable for thisembodiment are discussed in the references entitled “Soft Lithography,”by Younan Xia and George M. Whitesides, published in the Annual Reviewof Material Science, 1998, Vol. 28, pages 153-184, and “Soft Lithographyin Biology and Biochemistry,” by George M. Whitesides, Emanuele Ostuni,Shuichi Takayama, Xingyu Jiang and Donald E. Ingber, published in theAnnual Review of Biomedical Engineering, 2001, Vol. 3, pages 335-373;each of these references is incorporated herein by reference).

Other examples of potentially suitable polymers include, but are notlimited to, polyethylene terephthalate (PET), polyacrylate,polymethacrylate, polycarbonate, polystyrene, polyethylene,polypropylene, polyvinylchloride, cyclic olefin copolymer (COC),polytetrafluoroethylene, a fluorinated polymer, a silicone such aspolydimethylsiloxane, polyvinylidene chloride, bis-benzocyclobutene(“BCB”), a polyimide, a fluorinated derivative of a polyimide, or thelike. Combinations, copolymers, or blends involving polymers includingthose described above are also envisioned. The device may also be formedfrom composite materials, for example, a composite of a polymer and asemiconductor material.

In some embodiments, various components of the invention are fabricatedfrom polymeric and/or flexible and/or elastomeric materials, and can beconveniently formed of a hardenable fluid, facilitating fabrication viamolding (e.g. replica molding, injection molding, cast molding, etc.).The hardenable fluid can be essentially any fluid that can be induced tosolidify, or that spontaneously solidifies, into a solid capable ofcontaining and/or transporting fluids contemplated for use in and withthe fluidic network. In one embodiment, the hardenable fluid comprises apolymeric liquid or a liquid polymeric precursor (i.e. a “prepolymer”).Suitable polymeric liquids can include, for example, thermoplasticpolymers, thermoset polymers, waxes, metals, or mixtures or compositesthereof heated above their melting point. As another example, a suitablepolymeric liquid may include a solution of one or more polymers in asuitable solvent, which solution forms a solid polymeric material uponremoval of the solvent, for example, by evaporation. Such polymericmaterials, which can be solidified from, for example, a melt state or bysolvent evaporation, are well known to those of ordinary skill in theart. A variety of polymeric materials, many of which are elastomeric,are suitable, and are also suitable for forming molds or mold masters,for embodiments where one or both of the mold masters is composed of anelastomeric material. A non-limiting list of examples of such polymersincludes polymers of the general classes of silicone polymers, epoxypolymers, and acrylate polymers. Epoxy polymers are characterized by thepresence of a three-membered cyclic ether group commonly referred to asan epoxy group, 1,2-epoxide, or oxirane. For example, diglycidyl ethersof bisphenol A can be used, in addition to compounds based on aromaticamine, triazine, and cycloaliphatic backbones. Another example includesthe well-known Novolac polymers. Non-limiting examples of siliconeelastomers suitable for use according to the invention include thoseformed from precursors including the chlorosilanes such asmethylchlorosilanes, ethylchlorosilanes, phenylchlorosilanes, etc.

Silicone polymers are used in certain embodiments, for example, thesilicone elastomer polydimethylsiloxane. Non-limiting examples of PDMSpolymers include those sold under the trademark Sylgard by Dow ChemicalCo., Midland, Mich., and particularly Sylgard 182, Sylgard 184, andSylgard 186. Silicone polymers including PDMS have several beneficialproperties simplifying fabrication of the microfluidic structures of theinvention. For instance, such materials are inexpensive, readilyavailable, and can be solidified from a prepolymeric liquid via curingwith heat. For example, PDMSs are typically curable by exposure of theprepolymeric liquid to temperatures of about, for example, about 65° C.to about 75° C. for exposure times of, for example, about an hour. Also,silicone polymers, such as PDMS, can be elastomeric and thus may beuseful for forming very small features with relatively high aspectratios, necessary in certain embodiments of the invention. Flexible(e.g., elastomeric) molds or masters can be advantageous in this regard.

One advantage of forming structures such as microfluidic structures ofthe invention from silicone polymers, such as PDMS, is the ability ofsuch polymers to be oxidized, for example by exposure to anoxygen-containing plasma such as an air plasma, so that the oxidizedstructures contain, at their surface, chemical groups capable ofcross-linking to other oxidized silicone polymer surfaces or to theoxidized surfaces of a variety of other polymeric and non-polymericmaterials. Thus, components can be fabricated and then oxidized andessentially irreversibly sealed to other silicone polymer surfaces, orto the surfaces of other substrates reactive with the oxidized siliconepolymer surfaces, without the need for separate adhesives or othersealing means. In most cases, sealing can be completed simply bycontacting an oxidized silicone surface to another surface without theneed to apply auxiliary pressure to form the seal. That is, thepre-oxidized silicone surface acts as a contact adhesive againstsuitable mating surfaces. Specifically, in addition to beingirreversibly sealable to itself, oxidized silicone such as oxidized PDMScan also be sealed irreversibly to a range of oxidized materials otherthan itself including, for example, glass, silicon, silicon oxide,quartz, silicon nitride, polyethylene, polystyrene, glassy carbon, andepoxy polymers, which have been oxidized in a similar fashion to thePDMS surface (for example, via exposure to an oxygen-containing plasma).Oxidation and sealing methods useful in the context of the presentinvention, as well as overall molding techniques, are described in theart, for example, in an article entitled “Rapid Prototyping ofMicrofluidic Systems and Polydimethylsiloxane,” Anal. Chem., 70:474-480,1998 (Duffy et al.), incorporated herein by reference.

Another advantage to forming microfluidic structures of the invention(or interior, fluid-contacting surfaces) from oxidized silicone polymersis that these surfaces can be much more hydrophilic than the surfaces oftypical elastomeric polymers (where a hydrophilic interior surface isdesired). Such hydrophilic channel surfaces can thus be more easilyfilled and wetted with aqueous solutions than can structures comprisedof typical, unoxidized elastomeric polymers or other hydrophobicmaterials.

As described herein, any of a variety of signaling or display methods,associated with analyses, can be provided including signaling visually,by smell, sound, feel, taste, or the like, in one set of embodiments.Signal structures or generators include, but are not limited to,displays (visual, LED, light, etc.), speakers, chemical-releasingchambers (e.g., containing a volatile chemical), mechanical devices,heaters, coolers, or the like. In some cases, the signal structure orgenerator may be integral with the device (e.g., integrally connectedwith a deployment actuator for application to the skin of the subject,e.g., containing a substance transfer component such as a needle or amicroneedle), or the signal structure may not be integrally connectedwith the deployment actuator. As used herein, a “signal structure” or a“signal generator” is any apparatus able to generate a signal that isrelated to a condition of a medium. For example, the medium may be abodily fluid, such as blood or interstitial fluid.

In some embodiments, signaling methods such as these may be used toindicate the presence and/or concentration of an analyte determined bythe sensor, e.g., to the subject, and/or to another entity, such asthose described below. Where a visual signal is provided, it can beprovided in the form of change in opaqueness, a change in intensity ofcolor and/or opaqueness, or can be in the form of a message (e.g.,numerical signal, or the like), an icon (e.g., signaling by shape orotherwise a particular medical condition), a brand, logo, or the like.For instance, in one embodiment, the device may include a display. Awritten message such as “take next dose,” or “glucose level is high” ora numerical value might be provided, or a message such as “toxin ispresent.” These messages, icons, logos, or the like can be provided asan electronic read-out by a component of a device and/or can bedisplayed as in inherent arrangement of one or more components of thedevice.

In some embodiments, a device is provided where the device determines aphysical condition of a subject and produces a signal related to thecondition that can be readily understood by the subject (e.g., byprovision of a visual “OK” signal as described above) or can be designedso as not to be readily understandable by a subject. Where not readilyunderstandable, the signal can take a variety of forms. In one form, thesignal might be a series of letters or numbers that mean nothing to thesubject (e.g., A1278CDQ) which would have meaning to a medicalprofessional or the like (and/or be decodable by the same, e.g., withreference to a suitable decoder) and can be associated with a particularphysiological condition. Alternatively, a signal in the form of bar codecan be provided by a device such that, under a particular condition orset of conditions the bar code appears and/or disappears, or changes,and can be read by a bar code reader to communicate information aboutthe subject or analyte. In another embodiment, the device can bedesigned such that an ultraviolet signal is produced, or a signal thatcan be read only under ultraviolet light (e.g., a simple spot or patch,or any other signal such as a series of number, letters, bar code,message, or the like that can be readily understandable or not readilyunderstandable by a subject) can be provided. The signal may beinvisible to the human eye but, upon application UV light or otherexcitation energy, may be readable. The signal can be easily readable orunderstandable by a user via visual observation, or with other sensoryactivity such as smell, feel, etc. In another set of embodimentsequipment as described above may be needed to determine a signalprovided by the device, such as equipment in a clinical setting, etc. Insome cases, the device is able to transmit a signal indicative of theanalyte to a receiver, e.g., as a wireless signal, a radio signal, etc.

In some embodiments, quantitative and/or qualitative analyses can beprovided by a device. That is, the device in some cases may provideanalyses that allow “yes/no” tests or the like, or tests that provideinformation on the quantity, concentration, or level of a particularanalyte or analytes. Display configurations can be provided by theinvention that reflect the amount of a particular analyte present in asubject at a particular point in time, or any other variable (presenceof analysis over time, type of analyte, etc.) display configurations cantake a variety of forms. In one example, a dial can be provided, similarto that of a speedometer with a series of level indications (e.g.,numbers around the dial) and a “needle” or other device that indicates aparticular level. In other configurations, a particular area of thedevice (e.g., on a display) can exist that is filled in to a greater orlesser extent depending upon the presence and/or quantity of aparticular analyte present, e.g., in the form of a bar graph. In anotherarrangement a “color wheel” can be provided where the amount of aparticular analyte present can control which colors of the wheel arevisible. Or, different analytes can cause different colors of a wheel ordifferent bars of a graph to become visible or invisible in a multipleanalyte analysis. Multiple-analyte quantitative analyses can bereflected in multiple color wheels, a single color wheel with differentcolors per analyte where the intensity of each color reflects the amountof the analyte, or, for example, a plurality of bar graphs where eachbar graph is reflective of a particular analyte and the level of the bar(and/or degree to which an area is filled in with visible color or othervisible feature) is reflective of the amount of the analyte. As with allembodiments here, whatever signal is displayed can be understandable ornot understandable to any number of participants. For example, it can beunderstandable to a subject or not understandable to a subject. Wherenot understandable it might need to be decoded, read electronically, orthe like. Where read electronically, for example, a device may provide asignal that is not understandable to a subject or not even visible orotherwise able to be sensed by a subject, and a reader can be providedadjacent or approximate the device that can provide a visible signalthat is understandable or not understandable to the subject, or cantransmit a signal to another entity for analysis.

In connection with any signals associated with any analyses describedherein, another, potentially related signal or other display (or smell,taste, or the like) can be provided which can assist in interpretingand/or evaluating the signal. In one arrangement, a calibration orcontrol is provided proximate (or otherwise easily comparable with) asignal, e.g., a visual calibration/control or comparator next to orclose to a visual signal provided by a device and/or implanted agents,particles, or the like.

A visual control or reference can be used with another sensory signal,such as that of smell, taste, temperature, itch, etc. Areference/control and/or experimental confirmation component can beprovided, to be used in connection with an in-skin test or vice versa.References/indicators can also be used to indicate the state of life ofa device, changing color or intensity and/or changing in anothersignaling aspect as the device changes relative to its useful life, sothat a user can determine when the device should no longer be reliedupon and/or removed. For certain devices, an indicator or control can beeffected by adding analyte to the control (e.g., from a source outsideof the source to be determine) to confirm operability of the deviceand/or to provide a reference against which to measure a signal of thedevice. For example, a device can include a button to be tapped by auser which will allow an analyte from a reservoir to transfer to anindicator region to provide a signal, to demonstrate operability of thedevice and/or provide a comparator for analysis.

Many of the embodiments described herein involve a quantitative analysisand related signal, i.e., the ability to determine the relative amountor concentration of an analyte in a medium. This can be accomplished ina variety of ways. For example, where an agent (e.g. a binding partnerattached to a nanoparticle) is used to capture and analyze an analyte,the agent can be provided in a gradient in concentration across asensing region of the device. Or a sensing region can include a membraneor other apparatus through which analyte is required to flow or passprior to capture and identification, and the pathway for analyte travelcan vary as a function of position of display region. For example, amembrane can be provided across a sensing region, through which analytemust pass prior to interacting with a layer of binding and/or signalingagent, and the membrane may vary in thickness laterally in a directionrelated to “bar graph” readout. Where a small amount of analyte ispresent, it may pass through the thinner portion but not the thickerportion of the membrane, but where a larger amount is present, it maypass across a thicker portion. The boundary (where one exists) between aregion through which analyte passes, and one through which it does notcompletely pass, can define the “line” of the bar graph. Other ways ofachieving the same or a similar result can include varying theconcentration of a scavenger or transporter of the analyte, or anintermediate reactive species (between analyte and signaling event),across a membrane or other article, gradient in porosity or selectivityof the membrane, ability to absorb or transport sample fluid, or thelike. These principles, in combination with other disclosure herein, canbe used to facilitate any or all of the quantitative analyses describedherein.

In one set of embodiments, a subject having a condition such as aphysiological condition to be analyzed (or other user, such as medicalpersonnel) reads and/or otherwise determines a signal from a device. Forexample, the device may transmit a signal indicative of a condition ofthe subject and/or the device. Alternatively, or in addition, a signalproduced by a device can be acquired in the form of a representation(e.g. a digitized signal, or the like) and transmitted to another entityfor analysis and/or action. For example, a signal can be produced by adevice, e.g., based on a sensor reading of an analyte, based on fluiddelivered and/or received from the skin, based on a condition of thedevice, or the like. The signal may represent any suitable data orimage. For example, the signal may represent the presence and/orconcentration of an analyte in fluid received from a subject, the amountof fluid received from a subject and/or delivered to the subject, thenumber of times the device has been used, the battery life of thedevice, the amount of vacuum left in the device, the cleanliness orsterility of the device, the identity of the device (e.g., wheremultiple devices are given unique identification numbers, to preventcounterfeiting, accidental exchange of equipment to incorrect users,etc.), or the like. For instance, in one set of embodiments, an image ofthe signal (e.g., a visual image or photograph) can be obtained andtransmitted to a different entity (for example, a user can take a cellphone picture of a signal generated by the device and send it, via cellphone, the other entity).

The other entity that the signal is transmitted to can be a human (e.g.,a clinician) or a machine. In some cases, the other entity may be ableto analyze the signal and take appropriate action. In one arrangement,the other entity is a machine or processor that analyzes the signal andoptionally sends a signal back to the device to give direction as toactivity (e.g., a cell phone can be used to transmit an image of asignal to a processor which, under one set of conditions, transmits asignal back to the same cell phone giving direction to the user, ortakes other action). Other actions can include automatic stimulation ofthe device or a related device to dispense a medicament orpharmaceutical, or the like. The signal to direct dispensing of apharmaceutical can take place via the same used to transmit the signalto the entity (e.g., cell phone) or a different vehicle or pathway.Telephone transmission lines, wireless networks, Internet communication,and the like can also facilitate communication of this type.

As one specific example, a device may be a glucose monitor. As signalmay be generated by the device and an image of the signal captured by acell phone camera and then transmitted via cell phone to a clinician.The clinician may then determine that the glucose (or e.g., insulin)level is appropriate or inappropriate and send a message indicating thisback to the subject via cell phone.

Information regarding the analysis can also be transmitted to the sameor a different entity, or a different location simply by removing thedevice or a portion of the device from the subject and transferring itto a different location. For example, a device can be used in connectionwith a subject to analyze presence and/or amount of a particularanalyte. At some point after the onset of use, the device, or a portionof the device carrying a signal or signals indicative of the analysis oranalyses, can be removed and, e.g., attached to a record associated withthe subject. As a specific example, a patch or other device can be wornby a subject to determine presence and/or amount of one or more analytesqualitatively, quantitatively, and/or over time. The subject can visit aclinician who can remove the patch (or other device) or a portion of thepatch and attach it to a medical record associated with the subject.

According to various sets of embodiments, the device may be used once,or multiple times, depending on the application. For instance, obtainingsamples for sensing, according to certain embodiments of the invention,can be done such that sensing can be carried out continuously,discretely, or a combination of these. For example, where a bodily fluidsuch as blood or interstitial fluid is accessed for determination of ananalyte, fluid can be accessed discretely (i.e., as a single dose, onceor multiple times), or continuously by creating a continuous flow offluid which can be analyzed once or any number of times. Additionally,testing can be carried out once, at a single point in time, or atmultiple points in time, and/or from multiple samples (e.g., at multiplelocations relative to the subject).

Alternatively or in addition, testing can be carried out continuouslyover any number of points in time involving one or any number oflocations relative to the subject or other multiple samples. As anexample, one bolus or isolated sample, of fluid such as interstitialfluid can be obtained. From that fluid a test can be carried out todetermine whether a particular analyte or other agent exists in thefluid. Alternatively, two or more tests can be carried out involvingthat quantity of fluid to determine the presence and/or quantity of twoor more analytes, and any number of such tests can be carried out. Testsinvolving that quantity of fluid can be carried out simultaneously orover a period of time. For example, a test for a particular analyte canbe carried out at various points in time to determine whether the resultchanges over time, or different analytes can be determined at differentpoints in time.

In another example, a needle or a microneedle, or other device(s) can beused to access a fluid of a subject such as interstitial fluid. Fluidcan be drawn to a point of analysis and analyzed in any manner describedherein. For example, an analysis can be carried out once, to determinethe presence and/or quantity of a single analyte, or a number of testscan be carried out. From a single sample of fluid, a particular test ornumber of tests can be carried out essentially simultaneously, oranalyses can be carried out over time. Moreover, fluid can be drawncontinuously from the subject and one or more tests can be carried outof any number of points in time. A variety of reasons for carrying outone or more tests over the course of time exists, as would be understoodby those of ordinary skill in the art. One such reason is to determinewhether the quantity or another characteristic of an analyte is constantin a subject, or changes over time. A variety of specific techniques forcontinuous and/or discrete testing will be described herein.

In one set of embodiments, one or more materials, such as particles, aredelivered to the skin. Examples of suitable materials include, but arenot limited to, particles such as microparticles or nanoparticles, achemical, a drug or a therapeutic agent, a diagnostic agent, a carrier,or the like. The particles may be, for example, nanoparticles ormicroparticles, and in some cases, the particles may be anisotropicparticles. In some cases, a plurality of particles may be used, and insome cases, some, or substantially all, of the particles may be thesame. For example, at least about 10%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, at least about 95%, or at leastabout 99% of the particles may have the same shape, and/or may have thesame composition.

The particles may be used for a variety of purposes. For instance, theparticles may contain a diagnostic agent or a reaction entity able tointeract with and/or associate with an analyte, or another reactionentity, or other particles. Such particles may be useful, for example,to determine one or more analytes, such as a marker of a disease state,as discussed below. As another example, the particles may contain a drugor a therapeutic agent, positioned on the surface and/or internally ofthe particles, which may be released by the particles and delivered tothe subject. Specific examples of these and other embodiments arediscussed in detail below.

In some cases, materials such as particles may become embedded withinthe skin, for example, due to physical properties of the materials(e.g., size, hydrophobicity, etc.). Thus, in some cases, a depot ofmaterial may be formed within the skin, and the depot may be temporaryor permanent. For instance, materials within the depot may eventuallydegrade (e.g., if the material is biodegradable), enter the bloodstream,or be sloughed off to the environment, e.g., as the cells of the dermisdifferentiate to form new epidermis and accordingly push the materialtowards the surface of the skin. Thus, the depot of material may bepresent within the subject on a temporary basis (e.g., on a time scaleof days or weeks), in certain instances.

As mentioned, certain aspects of the present invention are generallydirected to particles such as anisotropic particles or colloids, whichcan be used in a wide variety of applications. For instance, theparticles may be present within the skin, or externally of the skin,e.g., in a device on the surface of the skin. The particles may includemicroparticles and/or nanoparticles. As discussed above, a“microparticle” is a particle having an average diameter on the order ofmicrometers (i.e., between about 1 micrometer and about 1 mm), while a“nanoparticle” is a particle having an average diameter on the order ofnanometers (i.e., between about 1 nm and about 1 micrometer. Theparticles may be spherical or non-spherical, in some cases. For example,the particles may be oblong or elongated, or have other shapes such asthose disclosed in U.S. patent application Ser. No. 11/851,974, filedSep. 7, 2007, entitled “Engineering Shape of Polymeric Micro- andNanoparticles,” by S. Mitragotri, et al.; International PatentApplication No. PCT/US2007/077889, filed Sep. 7, 2007, entitled“Engineering Shape of Polymeric Micro- and Nanoparticles,” by S.Mitragotri, et al., published as WO 2008/031035 on Mar. 13, 2008; U.S.patent application Ser. No. 11/272,194, filed Nov. 10, 2005, entitled“Multi-phasic Nanoparticles,” by J. Lahann, et al., published as U.S.Patent Application Publication No. 2006/0201390 on Sep. 14, 2006; orU.S. patent application Ser. No. 11/763,842, filed Jun. 15, 2007,entitled “Multi-Phasic Bioadhesive Nan-Objects as Biofunctional Elementsin Drug Delivery Systems,” by J. Lahann, published as U.S. PatentApplication Publication No. 2007/0237800 on Oct. 11, 2007, each of whichis incorporated herein by reference. Other examples of particles can beseen in U.S. patent application Ser. No. 11/272,194, filed Nov. 10,2005, entitled “Multi-phasic Nanoparticles,” by J. Lahann, et al.,published as U.S. Patent Application Publication No. 2006/0201390 onSep. 14, 2006; U.S. patent application Ser. No. 11/763,842, filed Jun.15, 2007, entitled “Multi-Phasic Bioadhesive Nan-Objects asBiofunctional Elements in Drug Delivery Systems,” by J. Lahann,published as U.S. Patent Application Publication No. 2007/0237800 onOct. 11, 2007; or U.S. Provisional Patent Application Ser. No.61/058,796, filed Jun. 4, 2008, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications,” by D. Levinson, each ofwhich is incorporated herein by reference. Other examples of particlescan be seen in U.S. patent application Ser. No. 11/272,194, filed Nov.10, 2005, entitled “Multi-phasic Nanoparticles,” by J. Lahann, et al.,published as U.S. Patent Application Publication No. 2006/0201390 onSep. 14, 2006; U.S. patent application Ser. No. 11/763,842, filed Jun.15, 2007, entitled “Multi-Phasic Bioadhesive Nan-Objects asBiofunctional Elements in Drug Delivery Systems,” by J. Lahann,published as U.S. Patent Application Publication No. 2007/0237800 onOct. 11, 2007; or U.S. Provisional Patent Application Ser. No.61/058,796, filed Jun. 4, 2008, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications,” by D. Levinson, each ofwhich is incorporated herein by reference.

In some cases, a pooled region of fluid, such as a suction blister, maybe formed in the skin to facilitate delivery and/or receiving of fluidfrom the skin. Thus, certain aspects of the present invention aregenerally directed to the creation of suction blisters or other pooledregions of fluid within the skin. In one set of embodiments, a pooledregion of fluid can be created between the dermis and epidermis of theskin. Suction blisters or other pooled regions may form in a manner suchthat the suction blister or other pooled region is not significantlypigmented in some cases, since the basal layer of the epidermis containsmelanocytes, which are responsible for producing pigments. Such regionscan be created by causing the dermis and the epidermis to at leastpartially separate, and as will be discussed below, a number oftechniques can be used to at least partially separate the dermis fromthe epidermis.

In one technique, a pool of interstitial fluid is formed between layersof skin of a subject and, after forming the pool, fluid is drawn fromthe pool by accessing the fluid through a layer of skin, for example,puncturing the outer layer of skin with a microneedle. Specifically, forexample, a suction blister can be formed and then the suction blistercan be punctured and fluid can be drawn from the blister. In anothertechnique, an interstitial region can be accessed and fluid drawn fromthat region without first forming a pool of fluid via a suction blisteror the like. For example, a microneedle or microneedles can be appliedto the interstitial region and fluid can be drawn there from.

Pooled regions of fluids may be formed on any suitable location withinthe skin of a subject. Factors such as safety or convenience may be usedto select a suitable location, as (in humans) the skin is relativelyuniform through the body, with the exception of the hands and feet. Asnon-limiting examples, the pooled region may be formed on an arm or aleg, on the chest, abdomen, or the back of the subject, or the like. Thesize of the pooled region of fluid that is formed in the skin and/or theduration that the pooled region lasts within the skin depends on avariety of factors, such as the technique of creating the pooled region,the size of the pooled region, the size of the region of skin to whichthe technique is applied, the amount of fluid received from the pooledregion (if any), any materials that are delivered into the pooledregion, or the like. For example, if vacuum is applied to the skin tocreate a suction blister, the vacuum applied to the skin, the durationof the vacuum, and/or the area of the skin affected may be controlled tocontrol the size and/or duration of the suction blister. In someembodiments, it may be desirable to keep the pooled regions relativelysmall, for instance, to prevent an unsightly visual appearance, to allowfor greater sampling accuracy (due to a smaller volume of material), orto allow for more controlled placement of particles within the skin. Forexample, the volume of the pooled region may be kept to less than about2 ml or less than about 1 ml in certain cases, or the average diameterof the pooled region (i.e., the diameter of a circle having the samearea as the pooled region) may be kept to less than about 5 cm, lessthan about 4 cm, less than about 3 cm, less than about 2 cm, less thanabout 1 cm, less than about 5 mm, less than about 4 mm, less than about3 mm, less than about 2 mm, or less than about 1 mm.

A variety of techniques may be used to cause pooled regions of fluid toform within the skin. In one set of embodiments, vacuum is applied tocreate a suction blister, or otherwise used to collect interstitialfluid from a subject. In other embodiments, however, other methods maybe used to create as a pooled region of fluid within the skin besides,or in addition to, the use of vacuum. When vacuum (i.e., the amount ofpressure below atmospheric pressure, such that atmospheric pressure hasa vacuum of 0 mmHg, i.e., the pressure is gauge pressure rather thanabsolute pressure) is used to at least partially separate the dermisfrom the epidermis to cause the pooled region to form, the pooled regionof fluid thus formed can be referred to as a suction blister. Forexample, vacuums of at least about 50 mmHg, at least about 100 mmHg, atleast about 150 mmHg, at least about 200 mmHg, at least about 250 mmHg,at least about 300 mmHg, at least about 350 mmHg, at least about 400mmHg, at least about 450 mmHg, at least about 500 mmHg, at least about550 mmHg, at least about 600 mmHg, at least about 650 mmHg, at leastabout 700 mmHg, or at least about 750 mmHg may be applied to the skin,e.g., to cause a suction blister and/or to collect interstitial fluidfrom a subject (as discussed, these measurements are negative relativeto atmospheric pressure. Different amounts of vacuum may be applied todifferent subjects in some cases, for example, due to differences in thephysical characteristics of the skin of the subjects.

The vacuum may be applied to any suitable region of the skin, and thearea of the skin to which the vacuum may be controlled in some cases.For instance, the average diameter of the region to which vacuum isapplied may be kept to less than about 5 cm, less than about 4 cm, lessthan about 3 cm, less than about 2 cm, less than about 1 cm, less thanabout 5 mm, less than about 4 mm, less than about 3 mm, less than about2 mm, or less than about 1 mm. In addition, such vacuums may be appliedfor any suitable length of time at least sufficient to cause at leastsome separation of the dermis from the epidermis to occur. For instance,vacuum may be applied to the skin for at least about 1 min, at leastabout 3 min, at least about 5 min, at least about 10 min, at least about15 min, at least about 30 min, at least about 1 hour, at least about 2hours, at least about 3 hours, at least about 4 hours, etc. Examples ofdevices suitable for creating such suction blisters are discussed inmore detail below. In other cases, however, bodily fluids such as bloodor interstitial fluid may be received from the skin using vacuum withoutthe creation of a suction blister. Other non-limiting fluids includesaliva, sweat, tears, mucus, plasma, lymph, or the like.

Other methods besides vacuum may be used to cause such separation tooccur. For example, in another set of embodiments, heat may be used. Forinstance, a portion of the skin may be heated to at least about 40° C.,at least about 50° C., at least about 55° C., or at least about 60° C.,using any suitable technique, to cause such separation to occur. Theskin may be heated, for instance, using an external heat source (e.g.,radiant heat or a heated water bath), a chemical reaction,electromagnetic radiation (e.g., microwave radiation, infraredradiation, etc.), or the like. In some cases, the radiation may befocused on a relatively small region of the skin, e.g., to at leastpartially spatially contain the amount of heating within the skin thatoccurs.

In yet another set of embodiments, a separation chemical may be appliedto the skin to at least partially cause separation of the dermis and theepidermis to occur. Non-limiting examples of such separation chemicalsinclude proteases such as trypsin, purified human skin tryptase, orcompound 48/80. Separation compounds such as these are commerciallyavailable from various sources. The separation chemical may be applieddirectly to the skin, e.g., rubbed into the surface of the skin, or insome cases, the separation chemical can be delivered into the subject,for example, between the epidermis and dermis of the skin. Theseparation chemical can, for example, be injected in between the dermisand the epidermis.

Another example of a separation chemical is a blistering agent, such aspit viper venom or blister beetle venom. Non-limiting examples ofblistering agents include phosgene oxime, Lewisite, sulfur mustards(e.g., mustard gas or 1,5-dichloro-3-thiapentane,1,2-bis(2-chloroethylthio)ethane, 1,3-bis(2-chloroethylthio)-n-propane,1,4-bis(2-chloroethylthio)-n-butane,1,5-bis(2-chloroethylthio)-n-pentane, 2-chloroethylchloromethylsulfide,bis(2-chloroethyl)sulfide, bis(2-chloroethylthio)methane,bis(2-chloroethylthiomethyl)ether, or bis(2-chloroethylthioethyl)ether),or nitrogen mustards (e.g., bis(2-chloroethyl)ethylamine,bis(2-chloroethyl)methylamine, or tris(2-chloroethyl)amine).

In still another set of embodiments, a device may be inserted into theskin and used to mechanically separate the epidermis and the dermis, forexample, a wedge or a spike. Fluids may also be used to separate theepidermis and the dermis, in yet another set of embodiments. Forexample, saline or another relatively inert fluid may be injected intothe skin between the epidermis and the dermis to cause them to at leastpartially separate.

These and/or other techniques may also be combined, in still otherembodiments. For example, in one embodiment, vacuum and heat may beapplied to the skin of a subject, sequentially and/or simultaneously, tocause such separation to occur. As a specific example, in oneembodiment, vacuum is applied while the skin is heated to a temperatureof between about 40° C. and about 50° C.

One aspect of the present invention is directed to an adaptor able toposition a device of the invention in apparatuses designed to containVacutainer™ tubes or Vacuette™ tubes. In some cases, the Vacutainer orVacuette tube sizes have a maximum length of no more than about 75 mm orabout 100 mm and a diameter of no more than about 16 mm or about 13 mm.In some cases, the adaptor may be able to immobilize a device of theinvention therein, e.g., for subsequent use or processing. In somecases, as previously discussed, devices of the invention may have alargest lateral dimension of no more than about 50 mm, and/or a largestvertical dimension, extending from the skin of the subject when thedevice is applied to the subject, of no more than about 10 mm. Anexample of such a device is shown in FIG. 9, with device 800 containedwithin adapter 850. The device may contained within the adaptor usingany suitable technique, e.g., using clips, springs, braces, bands, orthe application of force to the device present within the adaptor.

In another aspect, the present invention is directed to a kit includingone or more of the compositions previously discussed, e.g., a kitincluding a device for the delivery and/or receiving of fluid from theskin, a kit including a device able to create a pooled region of fluidwithin the skin of a subject, a kit including a device able to determinea fluid, or the like. An example of a kit containing more than onedevice of the invention is illustrated in FIG. 2D, with kit 150containing devices 152. A “kit,” as used herein, typically defines apackage or an assembly including one or more of the compositions ordevices of the invention, and/or other compositions or devicesassociated with the invention, for example, as previously described. Forexample, in one set of embodiments, the kit may include a device and oneor more compositions for use with the device. Each of the compositionsof the kit, if present, may be provided in liquid form (e.g., insolution), or in solid form (e.g., a dried powder). In certain cases,some of the compositions may be constitutable or otherwise processable(e.g., to an active form), for example, by the addition of a suitablesolvent or other species, which may or may not be provided with the kit.Examples of other compositions or components associated with theinvention include, but are not limited to, solvents, surfactants,diluents, salts, buffers, emulsifiers, chelating agents, fillers,antioxidants, binding agents, bulking agents, preservatives, dryingagents, antimicrobials, needles, syringes, packaging materials, tubes,bottles, flasks, beakers, dishes, frits, filters, rings, clamps, wraps,patches, containers, tapes, adhesives, and the like, for example, forusing, administering, modifying, assembling, storing, packaging,preparing, mixing, diluting, and/or preserving the compositionscomponents for a particular use, for example, to a sample and/or asubject.

A kit of the invention may, in some cases, include instructions in anyform that are provided in connection with the compositions of theinvention in such a manner that one of ordinary skill in the art wouldrecognize that the instructions are to be associated with thecompositions of the invention. For instance, the instructions mayinclude instructions for the use, modification, mixing, diluting,preserving, administering, assembly, storage, packaging, and/orpreparation of the compositions and/or other compositions associatedwith the kit. In some cases, the instructions may also includeinstructions for the delivery and/or administration of the compositions,for example, for a particular use, e.g., to a sample and/or a subject.The instructions may be provided in any form recognizable by one ofordinary skill in the art as a suitable vehicle for containing suchinstructions, for example, written or published, verbal, audible (e.g.,telephonic), digital, optical, visual (e.g., videotape, DVD, etc.) orelectronic communications (including Internet or web-basedcommunications), provided in any manner.

In some embodiments, the present invention is directed to methods ofpromoting one or more embodiments of the invention as discussed herein.As used herein, “promoted” includes all methods of doing businessincluding, but not limited to, methods of selling, advertising,assigning, licensing, contracting, instructing, educating, researching,importing, exporting, negotiating, financing, loaning, trading, vending,reselling, distributing, repairing, replacing, insuring, suing,patenting, or the like that are associated with the systems, devices,apparatuses, articles, methods, compositions, kits, etc. of theinvention as discussed herein. Methods of promotion can be performed byany party including, but not limited to, personal parties, businesses(public or private), partnerships, corporations, trusts, contractual orsub-contractual agencies, educational institutions such as colleges anduniversities, research institutions, hospitals or other clinicalinstitutions, governmental agencies, etc. Promotional activities mayinclude communications of any form (e.g., written, oral, and/orelectronic communications, such as, but not limited to, e-mail,telephonic, Internet, Web-based, etc.) that are clearly associated withthe invention.

In one set of embodiments, the method of promotion may involve one ormore instructions. As used herein, “instructions” can define a componentof instructional utility (e.g., directions, guides, warnings, labels,notes, FAQs or “frequently asked questions,” etc.), and typicallyinvolve written instructions on or associated with the invention and/orwith the packaging of the invention. Instructions can also includeinstructional communications in any form (e.g., oral, electronic,audible, digital, optical, visual, etc.), provided in any manner suchthat a user will clearly recognize that the instructions are to beassociated with the invention, e.g., as discussed herein.

The following documents are incorporated herein by reference: U.S.Provisional Patent Application Ser. No. 61/334,533, filed May 13, 2010,entitled “Rapid Delivery and/or Withdrawal of Fluids,” by Chickering, etal.; U.S. Provisional Patent Application Ser. No. 61/334,529, filed May13, 2010, entitled “Sampling Device Interfaces,” by Chickering, et al.;U.S. Provisional Patent Application Ser. No. 61/357,582, filed Jun. 23,2010, entitled “Sampling Devices and Methods Involving Relatively LittlePain,” by Chickering, et al.; U.S. Provisional Patent Application Ser.No. 61/367,607, filed Jul. 26, 2010, entitled “Microneedles andTechniques for Making and Using Same,” by Davis, et al.; U.S.Provisional Patent Application Ser. No. 61/373,764, filed Aug. 13, 2010,entitled “Clinical and/or Consumer Techniques and Devices,” byChickering, et al.; U.S. Provisional Patent Application Ser. No.61/058,796, filed Jun. 4, 2008, entitled “Compositions and Methods forDiagnostics, Therapies, and Other Applications”; U.S. Provisional PatentApplication Ser. No. 61/163,791, filed Mar. 26, 2009, entitled“Composition and Methods for Rapid One-Step Diagnosis”; U.S. ProvisionalPatent Application Ser. No. 61/163,793, filed Mar. 26, 2009, entitled“Compositions and Methods for Diagnostics, Therapies, and OtherApplications”; U.S. patent application Ser. No. 12/478,756, filed Jun.4, 2009, entitled “Compositions and Methods for Diagnostics, Therapies,and Other Applications”; International Patent Application No.PCT/US09/046333, filed Jun. 4, 2009, entitled “Compositions and Methodsfor Diagnostics, Therapies, and Other Applications”; U.S. ProvisionalPatent Application Ser. No. 61/163,710, filed Mar. 26, 2009, entitled“Systems and Methods for Creating and Using Suction Blisters or OtherPooled Regions of Fluid within the Skin”; U.S. Provisional PatentApplication Ser. No. 61/163,733, filed Mar. 26, 2009, entitled“Determination of Tracers within Subjects”; U.S. Provisional PatentApplication Ser. No. 61/163,750, filed Mar. 26, 2009, entitled“Monitoring of Implants and Other Devices”; U.S. Provisional PatentApplication Ser. No. 61/154,632, filed Mar. 2, 2009, entitled “OxygenSensor”; and U.S. Provisional Patent Application Ser. No. 61/269,436,filed Jun. 24, 2009, entitled “Devices and Techniques associated withDiagnostics, Therapies, and Other Applications, IncludingSkin-Associated Applications.” Also incorporated by reference herein areU.S. Provisional Patent Application Ser. No. 61/263,882, filed Nov. 24,2009, entitled “Patient-Enacted Sampling Technique”; U.S. ProvisionalPatent Application Ser. No. 61/294,543, filed Jan. 13, 2010, entitled“Blood Sampling Device and Method”; U.S. patent application Ser. No.12/716,222, filed Mar. 2, 2010, entitled “Oxygen Sensor,” by Levinson,et al.; U.S. patent application Ser. No. 12/716,233, filed Mar. 2, 2010,entitled “Systems and Methods for Creating and Using Suction Blisters orOther Pooled Regions of Fluid within the Skin,” by Levinson, et al.;U.S. patent application Ser. No. 12/716,226, filed Mar. 2, 2010,entitled “Techniques and Devices Associated with Blood Sampling,” byLevinson, et al.; and U.S. patent application Ser. No. 12/716,229, filedMar. 2, 2010, entitled “Devices and Techniques Associated withDiagnostics, Therapies, and Other Applications, IncludingSkin-Associated Applications,” by Bernstein, et al.

Also incorporated herein by reference is U.S. Provisional PatentApplication Ser. No. 61/411,566, filed Nov. 9, 2010, entitled “Systemsand Interfaces for Blood Sampling,” by David Brancazio.

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

All definitions, as defined and used herein, should be understood tocontrol over dictionary definitions, definitions in documentsincorporated by reference, and/or ordinary meanings of the definedterms.

The indefinite articles “a” and “an,” as used herein in thespecification and in the claims, unless clearly indicated to thecontrary, should be understood to mean “at least one.”

The phrase “and/or,” as used herein in the specification and in theclaims, should be understood to mean “either or both” of the elements soconjoined, i.e., elements that are conjunctively present in some casesand disjunctively present in other cases. Multiple elements listed with“and/or” should be construed in the same fashion, i.e., “one or more” ofthe elements so conjoined. Other elements may optionally be presentother than the elements specifically identified by the “and/or” clause,whether related or unrelated to those elements specifically identified.Thus, as a non-limiting example, a reference to “A and/or B”, when usedin conjunction with open-ended language such as “comprising” can refer,in one embodiment, to A only (optionally including elements other thanB); in another embodiment, to B only (optionally including elementsother than A); in yet another embodiment, to both A and B (optionallyincluding other elements); etc.

As used herein in the specification and in the claims, “or” should beunderstood to have the same meaning as “and/or” as defined above. Forexample, when separating items in a list, “or” or “and/or” shall beinterpreted as being inclusive, i.e., the inclusion of at least one, butalso including more than one, of a number or list of elements, and,optionally, additional unlisted items. Only terms clearly indicated tothe contrary, such as “only one of” or “exactly one of,” or, when usedin the claims, “consisting of,” will refer to the inclusion of exactlyone element of a number or list of elements. In general, the term “or”as used herein shall only be interpreted as indicating exclusivealternatives (i.e. “one or the other but not both”) when preceded byterms of exclusivity, such as “either,” “one of,” “only one of,” or“exactly one of.” “Consisting essentially of,” when used in the claims,shall have its ordinary meaning as used in the field of patent law.

As used herein in the specification and in the claims, the phrase “atleast one,” in reference to a list of one or more elements, should beunderstood to mean at least one element selected from any one or more ofthe elements in the list of elements, but not necessarily including atleast one of each and every element specifically listed within the listof elements and not excluding any combinations of elements in the listof elements. This definition also allows that elements may optionally bepresent other than the elements specifically identified within the listof elements to which the phrase “at least one” refers, whether relatedor unrelated to those elements specifically identified. Thus, as anon-limiting example, “at least one of A and B” (or, equivalently, “atleast one of A or B,” or, equivalently “at least one of A and/or B”) canrefer, in one embodiment, to at least one, optionally including morethan one, A, with no B present (and optionally including elements otherthan B); in another embodiment, to at least one, optionally includingmore than one, B, with no A present (and optionally including elementsother than A); in yet another embodiment, to at least one, optionallyincluding more than one, A, and at least one, optionally including morethan one, B (and optionally including other elements); etc.

It should also be understood that, unless clearly indicated to thecontrary, in any methods claimed herein that include more than one stepor act, the order of the steps or acts of the method is not necessarilylimited to the order in which the steps or acts of the method arerecited.

In the claims, as well as in the specification above, all transitionalphrases such as “comprising,” “including,” “carrying,” “having,”“containing,” “involving,” “holding,” “composed of,” and the like are tobe understood to be open-ended, i.e., to mean including but not limitedto. Only the transitional phrases “consisting of” and “consistingessentially of” shall be closed or semi-closed transitional phrases,respectively, as set forth in the United States Patent Office Manual ofPatent Examining Procedures, Section 2111.03.

What is claimed is: 1-192. (canceled)
 193. A device for receiving bloodfrom a subject, the device comprising: an actuator; a flexible concavemember, wherein the flexible concave member is moveable between a firstconfiguration and a second configuration upon actuation of the actuator;a needle, wherein the needle is in a first position before actuation ofthe actuator and in a second position after actuation of the actuator;an applicator region containing the needle at least when the needle isin the second position; and an evacuated vacuum tube having a pressureless than atmospheric pressure before the device is actuated.
 194. Thedevice of claim 193, wherein the needle is a microneedle.
 195. Thedevice of claim 193, wherein the evacuated vacuum tube is removable fromthe device.
 196. The device of claim 193, wherein the device isconfigured such that movement of the flexible concave member from thefirst configuration to the second configuration inserts the needle intothe subject's skin and creates a fluid communication pathway between theevacuated vacuum tube and the applicator region.
 197. The device ofclaim 193, wherein the device further comprises a retraction mechanismable to move the needle towards the first position after the needlereaches the second position.
 198. The device of claim 193, wherein theflexible concave member is able to spontaneously return from the secondconfiguration to the first configuration.
 199. The device of claim 193,wherein the evacuated vacuum tube has a pressure of less than 50 mmHgbelow atmospheric pressure.
 200. The device of claim 193, wherein theevacuated vacuum tube has a maximum length of no more than about 100 mmand a diameter of no more than about 16 mm.
 201. The device of claim193, wherein the evacuated vacuum tube contains an anticoagulant.
 202. Adevice for receiving blood from a subject, comprising: an actuator; aflexible concave member, wherein the flexible concave member is moveablebetween a first configuration and a second configuration upon actuationof the actuator; a needle, wherein the needle is in a first positionbefore actuation of the actuator and in a second position afteractuation of the actuator; an evacuated vacuum tube having a pressureless than atmospheric pressure before the device is actuated; and avacuum interface to which the subject's skin is drawn when vacuum isapplied to the skin from the evacuated vacuum tube.
 203. The device ofclaim 202, wherein the needle is a microneedle.
 204. The device of claim202, wherein the vacuum interface contains the needle when the needle isin the second position.
 205. The device of claim 202, wherein theevacuated vacuum tube has a pressure of less than 50 mmHg belowatmospheric pressure.
 206. The device of claim 202, wherein theevacuated vacuum tube contains an anticoagulant.
 207. The device ofclaim 202, wherein the device is configured such that movement of theflexible concave member from the first configuration to the secondconfiguration inserts the needle into the subject's skin and creates afluid communication pathway between the evacuated vacuum tube and thevacuum interface.
 208. A method, comprising: attaching an evacuatedvacuum tube having a pressure less than atmospheric pressure to a devicecomprising an actuator, a needle, and an applicator region; applying thedevice to a subject's skin; and actuating the actuator to cause thedevice to mechanically move the needle into the applicator region andinsert the needle into the skin, and to create a fluid communicationpathway within the device between the applicator region and theevacuated vacuum tube to cause blood to be withdrawn into the device.209. The method of claim 208, wherein the needle is a microneedle. 210.The method of claim 208, further comprising removing the evacuatedvacuum tube from the device.
 211. The method of claim 208, wherein theevacuated vacuum tube has a pressure of less than 50 mmHg belowatmospheric pressure.
 212. The method of claim 208, wherein theevacuated vacuum tube contains an anticoagulant.